CA2629751A1 - Antimicrobial peptides - Google Patents

Abstract

A novel class of peptides having antimicrobial activity is provided. Also provided are methods for inhibiting the growth of bacteria utilizing the peptides of the invention. Pharmaceutical compositions comprising the novel class of peptides are also provided.

Description

ANTIMICROBIAL PEPTIDES
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority, under 35 USC 119(e), to U.S.
Application No. 60/627,356, filed November 12, 2004, the disclosure of which is incorporated by reference in its entirety.

FIELD

[0002] The present invention relates generally to peptides and more specifically to antimicrobial peptides.

BACKGROUND

[0003] The treatment of bacterial infections with antibiotics is one of the mainstays of human medicine. Unfortunately the effectiveness of antibiotics has become limited due to an increase in bacterial antibiotic resistance in the face of a dearth of discovery of new classes of antibiotics. Today, nosocomial bacterial infections that are resistant to therapy lead to costs of more than $2 billion, and account for more than 80,000 direct and indirect deaths in North America.

[0004] A major limitation in antibiotic development has been the difficulty in finding new structures with the same assets as conventional antibiotics, namely low toxicity for the host and a broad action against bacterial pathogens. Recent novel antibiotic classes, including the oxazolidinones (linezolid), the streptogramins (synercid) and the glycolipids (daptomycin) have all been limited in their spectrum of activity to Gram-positive pathogens. It is therefore a difficult challenge for scientists to design antibiotics with novel structures and/or modes of action.

[0005] Cationic antimicrobial peptides represent good templates for a new generation of antimicrobials. They kill both Gram negative and Gram positive microorganisms rapidly and directly, do not easily select mutants, work against common clinically-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococcus (VRE), show a synergistic effect with conventional antibiotics, and can often activate host innate immunity without displaying immunogenicity. Moreover, they seem to counteract some of the more harmful aspects of inflammation (e.g., sepsis, endotoxaemia), which is extremely important since rapid killing of bacteria and subsequent liberation of bacterial components such as LPS or peptidoglycan can induce fatal immune dysregulation (Jarisch-Herxheimer reaction).

[0006] Cationic antimicrobial peptides comprising sequences of natural L-amino acids were discovered in the hemolymph of insects in the late 1970s. Today, more than 600 cationic peptides have been described in bacteria, fungi, insects, tunicates, amphibians, crustaceans, birds, fish and mammals including humans. They can be described through their physical chemical characteristics with a size ranging from 12 to 50 amino acids, a net positive charge exceeding +2, due to excess arginine and lysine residues, and approximately 50% hydrophobic amino acids. The multitude of cationic peptide sources, structures and spectra of activity is matched by a number of complex and controversial models attempting to describe and explain the modes of action of these peptides. Most antimicrobial peptides bind to the lipopolysaccharide (LPS) of Gram-negative bacteria or to lipoteichoic acid of Gram-positives, and subsequently associate with and either permeabilize the cytoplasmic membrane or cross that membrane and act on internal targets. The precise mechanisms as to how they bring about death in target cells are not fully understood to date.

[0007] Recently, cationic peptides containing a disulphide bond forming a looped structure were identified. One member of this group, bactenecin (i.e., dodecapeptide), is a twelve amino acid peptide isolated from bovine neutrophils.
Bactenecin is the smallest known cationic antimicrobial peptide. Two cysteine residues form a disulphide bond to make bactenecin a loop molecule. This peptide is active against both Gram negative (E. coli, P. aeruginosa) and Gram positive bacteria (S.
pyogenes, C.
xerosis). It was demonstrated that the linear variant Bac2A shows a similar activity against Gram-negative bacteria and an improved activity against Gram-positive bacteria. These features, its small size, linearity and activity against both Gram-positive and Gram-negative bacteria make this peptide an ideal candidate for semi-random design methods such as spot peptide synthesis on cellulose membranes.

[0008] There is a need to develop peptides having a broad range of potent antimicrobial activity against a plurality of microorganisms, including Gram negative bacteria, Gram positive bacteria, fungi, protozoa, viruses and the like.

SIJMMARY

[0009] The present invention generally relates to peptides, and more specifically to antimicrobial peptides, analogs, derivatives, amidated variations and conservative variations thereof that have antimicrobial activity against a plurality of microorganisms, including Gram-negative bacteria, Gram-positive bacteria, fungi, protozoa and the like.
The present invention provides peptide-based compositions, peptide variant compositions, and peptide mimetic compositions that inhibit, prevent, or destroy the growth or proliferation of microbes such as bacteria, ftmgi, protozoa, viruses, parasites and the like, and are, therefore, useful in a variety of therapeutic applications as well as in other applications, including protecting objects from bacterial colonization. The therapeutic applications include the treatment of microbial related diseases and conditions wherein the amount of peptide used is of sufficient quantity to decrease the numbers of bacteria, viruses, fungi, and parasites in the body of a subject. The present invention also provides polypeptide compositions, functional variants, and peptide mimetics thereof.

[0010] The present invention is based on the discovery that certain peptides originally identified from bactenecin have antimicrobial activity. Exemplary peptides of the invention include peptides having the amino acid sequences of SEQ ID NOS:
2-2166, and analogs, derivatives, amidated variations and conservative variations thereof.

[0011] Accordingly, the present invention provides methods for treating microbial diseases, disorders and conditions by administering therapeutic compounds, e.g., pharmaceutical compositions comprising one or more antimicrobial peptides or proteins of the invention, to a subject.

[0012] The invention also provides a method of inhibiting the growth of bacteria including contacting the bacteria with an inhibiting effective amount of at least one peptide of the invention alone, or in combination with at least one antibiotic. Classes of antibiotics that can be used in synergistic therapy with the peptides of the invention include, but are not limited to, aminoglycoside, penicillin, cephalosporin, fluoroquinolone, carbepenem, tetracycline and macrolide.

[0013] The invention provides polynucleotides that encode the peptides of the invention. Exemplary polynucleotides encode peptides having the amino acid sequences of SEQ ID NOS: 2-2166, and analogs, derivatives and conservative variations thereof.

[0014] In one aspect, the invention provides an isolated antimicrobial peptide having 8 to 12 amino acids, wherein the peptide has an amino acid sequence of SEQ ID
NOS: 1-2166, or analogs, derivatives, amidated variations and conservative variations thereof. In some embodiments, an isolated polynucleotide encodes such peptides. In other embodiments, the peptide comprises any contiguous sequence of amino acids having the formula: Rl-L2-A3-R4-I5-V6-V7-I8-R9-V 1o-A11-R12, wherein R1= R or W; L2 = L, C, G, H, K, R, S, W, or Y; A3 = A, C, F, H, I, K, L, Q, R, or W; 15 =1, C, R, or W; V6 =V, C, F, or W;V7=V,C,H,I,K,N,Q,R,orT;I8=IorC;R9=RorC;V10=V,C,orW;A11=A, C, G, H, I, K, L, M, R, S, or Y, and derivatives, substitutions, deletions and additions thereof. In some embodiments, the peptide has an amino acid sequence having the formula: AA1 - AA2 - AA3 - AA4 - AA5 - AA6 - AA7 - AA8 - AA9 -AA10 - AA11 -AA12, wherein AAl = A, G, I, K, L, P, R, or W; AA2 = any residue except D, E, M, or N; AA3 =
any residue; AA4 = K, M, or R; AA5 = C, I, K, R, V, or W; AA6 = C, F, K, R, V, W, or Y;
AA7=C,F,G,H,I,K,L,N,Q,R,T,V,orY;AA8=C,F,I,K,R,V,W,orY;AA9=C, K, or R; AA10 = C, I, K, L, R, V, W, or Y; AA11 any residue except D, E, or P;
AA12 =
A, or R, and derivatives, substitutions, deletions and additions thereof. In other embodiments, the peptide has a sequence of 8 amino acids having the formula:

- AA3 - V- I- AA6 - AA7 - R, wherein AA1 = K or R; AA2 = I or R; AA3 = W or V;

=RorW;andAA7=RorW.

[0015] In another aspect, the invention provides a polypeptide Xl- A -X2 or a functional variant or mimetic thereof, wherein A represents at least one peptide having an amino acid sequence of SEQ ID NOS: 1-2166 or analogs, derivatives, amidated variations and conservative variations thereof; and wherein each Xl and X2 independently of one another represents any amino acid sequence of n amino acids, n varying from 0 to 50, and n being identical or different in Xl and X2. In some embodiments, the functional variant or mimetic is a conservative amino acid substitution or peptide mimetic substitution. In other embodiments, the functional variant has about 70% or greater amino acid identity to Xl- A
-X2. In some embodiments, n is zero.

[0016] In another aspect, the invention provides a method of inhibiting the growth of bacteria comprising contacting the bacteria with an inhibiting effective amount of a peptide having an amino acid sequence of SEQ ID NOS: 2-2166, or any combination thereof, or analogs, derivatives, amidated variations and conservative variations thereof, with the proviso that the peptide having an amino acid sequence of SEQ ID NO:
1 is only used in combination with any peptide having an amino acid sequence of SEQ ID
NO: 2-2166. In some embodiments, the contacting comprises a peptide in combination with at least one antibiotic or lysozome. In other embodiments, the antibiotic is selected from the group consisting of aminoglycosides, penicillins, cephalosporins, carbapenems, monobactams, quinolones, tetracyclines, and glycopeptides. In some embodiments, antibiotic is selected from the group consisting of amikacin, gentamicin, kanamycin, netilmicin, tobramycin, streptomycin, azithromycin, clarithromycin, erythromycin, erythromycin estolate/ethyl-succinate/gluceptate/lactobionate/stearate, penicillin G, penicillin V, methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin, ampicillin, amoxicillin, ticarcillin, carbenicillin, mezlocillin, azlocillin, piperacillin, cephalothin, cefazolin, cefaclor, cefamandole, cefoxitin, cefuroxime, cefonicid, cefmetazole, cefotetan, cefprozil, loracarbef, cefetamet, cefoperazone, cefotaxime, ceftizoxime, ceftriaxone, ceftazidime, cefepime, cefixime, cefpodoxime, cefsulodin, imipenem, aztreonam, fleroxacin, nalidixic acid, norfloxacin, ciprofloxacin, ofloxacin, enoxacin, lomefloxacin, cinoxacin, doxycycline, minocycline, tetracycline, vancomycin, chloramphenicol, clindamycin, trimethoprim, sulfamethoxazole, nitrofurantoin, rifampin and mupirocin and teicoplanin. In some embodiments, the bacteria is Gram positive. In some such embodiments, the bacteria is Staphylococcus aureus, Staplaylococcus epidermidis, or Enterococcusfaecaelis. In other embodiments, the bacteria Gram negative. In some such embodiments, the bacteria is Pseudomonas aeruginosa, Escherichia coli, or Salmonella enteritidis ssp Typhimurium. In other embodiments, the peptide is covalently bound to a solid support.

[0017] In another aspect, the invention provides a method of identifying an antimicrobial peptide having 8 to 12 amino acids that is derived from Bac2A.
The method includes contacting a test peptide with a microbe under conditions sufficient for antimicrobial activity, and detecting a change in growth or proliferation of the microbe as compared to the growth or proliferation of the microbe prior to contacting with the test peptide. In one embodiment, the peptide is synthesized in a multi-spot format on a solid support. The peptides of the invention will retain antimicrobial activity when cleaved from the solid support or retain activity when still associated with the solid support. In another embodiment, the peptide has a sequence of 12 amino acids including a consecutive stretch of 5 or more hydrophobic amino acid residues. The microbe can be a Gram negative bacterium, such as Pseudomonas aeruginosa, Escherichia coli, or Salmonella enteritidis ssp Typhimurium. In another embodiment, the microbe can be a Gram positive bacterium, such as Staphylococcus aureus, Staphylococcus epidermidis, or Enterococcus faecaelis. In yet another embodiment, the microbe can be a yeast, such as Candida albicans.
The detection can include detecting luminescence in a microtiter plate luminescence reader over time. In this embodiment, the microbe contains a reporter system, such as a bacterial luciferase construct inserted into the chromosome. For example, the bacterial luciferase construct is inserted into the fliC gene in Pseudoinonas aeruginosa.

[0018] In another aspect, the invention provides a pharmaceutical composition comprising the peptide(s) or polypeptide(s) of the invention and a pharmaceutically acceptable carrier.

[0019] In another aspect, the invention provides a method of modulating microbial activity in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the peptide(s) or polypeptide(s) of the invention and a pharmaceutically acceptable carrier.

[0020] In another aspect, the invention provides a method of treating a disease or disorder in a subject associated with microbial activity comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the peptide(s) or polypeptide(s) of the invention and a pharmaceutically acceptable carrier. In some embodiments, the method of treating comprises the pharmaceutical composition of the invention in combination or in conjunction with other drugs or agents that can be used to for preventing or treating disease or disorder in a subject or organism.

[0021] In another aspect, the invention provides a method of protecting medical devices from colonization with pathogenic bacteria by coating at least one peptide of the invention on the surface of the medical device.

BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Fig. 1A is a graphical representation showing the results of a killing assay of Pseudomonas aeruginosa strain H1001 using luciferase as a reporter of residual ATP
levels in the cell. These data demonstrate that the rate of killing (loss of luciferase activity as revealed by decreased light output in real time) is proportional to the amount of peptide added to the cells.

[0023] Fig. 1B is a graphical representation showing a conventional killing curve measuring residual colony counts by plating survivors on nutrient agar and growing overnight at 37oC.

[0024] Fig. 2 is a graphical representation showing the detection of the luminescence of Pseudomonas aeruginosa strain H1001 with cellulose bound peptides and controls after three hours incubation at 37 C.

[0025] Fig. 3A is a graphical representation showing the structural characterization of peptides by circular dichroism in buffer.

[0026] Fig. 3B is a graphical representation showing the structural characterization of peptides by circular dichroism in a lipid mimic, SDS.

[0027] Fig. 3C is a graphical representation showing the structural characterization of different scrambled peptides by circular dichroism spectroscopy in liposomes at increasing lipid to peptide ratios.

[0028] Fig. 4 is a graphical representation showing the mechanism of action of peptides assessed by measuring the ability to depolarize Staphylococcus aureus cells using the membrane potential-sensitive dye diSC35. Either 20 g/ml of peptides or, as a control, 29 g/ml of gramicidin S (Gram S) were added. Lines are smoothed using a poloynomial (to the 6th power) function.
[0029] Fig. 5 is a graphical representation showing the cytotoxicity on THP-1 macrophage-like cells as assessed by tryphan blue staining.

[0030] Fig. 6A is a graphical representation showing length analysis with bound peptides - longer peptides.

[0031] Fig. 6B is a graphical representation showing length analysis with bound peptides - shorter peptides.

[0032] Fig. 7 is a graphical representation showing complete substitution analysis of Bac2A.

[0033] Fig. 8 is a graphical representation showing assessment of the ability of peptides to bind to LPS as reflected by their suppression of P. aeruginosa LPS-stimulated TNFa production in THP1 cells. Presented results are the mean values for 4 wells performed on 2 separate occasions.
DETAILED DESCRIPTION

A. INTRODUCTION [0034] The present invention provides peptides having antimicrobial activity.

These peptides are useful for inhibiting microbial infection or growth and are often synergistic with conventional antibiotics and/or lysozyme. In addition, such peptides are useful as antifungal agents, antitumor agents, or antiviral agents. Many of the peptides of the invention are cationic in nature.
[0035] A method of synthesizing an array of peptides in parallel on cellulose sheets was developed by Ronald Frank in 1992. Frank, Tetrahedron 48: 9217-9232, 1992.
This technique was first carried out manually and used for the identification of antibody epitopes. Now, with the help of pipetting robots, up to 8000 peptides can be synthesized on one cellulose sheet (20x30 cm). Kramer et al., Cell 91: 799-809, 1997.
Today, the applications of this technology include characterizing homodimer interfaces, screening for kinase recognition sites, optimizing protease inhibitors, and screening for DNA binding sites of proteins.

[0036] The present invention adapts this methodology to create a large number of variants through sequence scrambling, truncations and systematic modifications of peptide sequence, and uses a luciferase-based screen to investigate their ability to kill Pseudomonas aeruginosa. This broad screening program represents a rapid and efficient method to investigate antimicrobial peptide activity. It has permitted for the first time a systematic and highly detailed investigation of the determinants of peptide activity in very small peptides. Previous attempts to make smaller peptides have tended to create molecules with modest activities or with good activities only when measured in dilute medium.

[0037] The peptides of the invention retain activities in the typical media used to test in vitro antibiotic activity, making them candidates for clinical therapeutic usage. In addition some of the peptides remain effective when bound to cellulose sheets, indicating that they have huge potential for use in coating medical devices, including catheters, to prevent them from becoming colonized with pathogenic bacteria.
[0038] The invention provides a number of methods, reagents, and compounds that can be used for inhibiting microbial infection or growth. It is to be understood that this invention is not limited to particular methods, reagents, compounds, compositions, or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "a peptide" includes a combination of two or more peptides, and the like.

[0039] "About" as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of 20% or 10%, more preferably 5%, even more preferably 1%, and still more preferably 0.1%
from the specified value, as such variations are appropriate to perform the disclosed methods.

[0040] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present invention, the preferred materials and methods are described herein. In describing and claiming the present invention, the following terminology will be used.
[0041] "Antimicrobial" as used herein means that the peptides of the present invention inhibit, prevent, or destroy the growth or proliferation of microbes such as bacteria, fungi, viruses, parasites or the like. "Antiviral" as used herein means that the peptides of the present invention inhibit, prevent or destroy the growth or proliferation of viruses or of virally-infected cells. "Anti-tumor" as used herein means that the peptides of the present invention may be used to inhibit the growth of or destroy tumors.
"Antifungal"
as used herein means that the peptides of the present invention may be used to inhibit the growth of or destroy fungi. "Antiparasite" as used herein means that the peptides of the present invention inhibit, prevent, or destroy the growth or proliferation of any organism that lives at the expense of a host organism.
[0042] As used herein, "microbe" or "microbial agent" is meant to include any organism comprised of the phylogenetic domains bacteria and archaea, as well as unicellular and filamentous fungi (such as yeasts and molds), unicellular and filamentous algae, unicellular and multicellular parasites, and viruses that causes a disease, disorder or condition in a subject. Accordingly, such microbial agents include, but are not limited to, bacterial, viral, fungal, or protozoan pathogens.
[0043] The compositions of the present invention possess activity toward microbes, i.e., antimicrobial activity. "Prevention" can be considered to be the obstruction or hindrance of any potential microbial growth. "Termination" can be considered to be actual killing of the microbes by the presence of the composition.
"Inhibition" can be considered to be a reduction in microbial growth or inhibiting virulence factor expression or function of the microbe. Preferably, the compositions of the present invention will inhibit virulence factor expression or function of a microbe by greater than 30%, 50%, 65%, 70%, 75%, 80%, 85%, 90%, more preferably by greater than 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%.
[0044] The present invention is effective against bacteria including Gram-positive and Gram-negative cocci, Gram-positive and Gram-negative straight, curved and helical/vibroid and branched rods, sheathed bacteria, sulfur-oxidizing bacteria, sulfur or sulfate-reducing bacteria, spirochetes, actinomycetes and related genera, myxobacteria, mycoplasmas, rickettsias and chlamydias, cyanobacteria, archea, fungi, parasites, viruses and algae.
[0045] The "amino acid" residues identified herein are in the natural L-configuration. In keeping with standard polypeptide nomenclature, J. Biol.
Chem. 243:
3557-59, 1968, abbreviations for amino acid residues are as shown in the following table.

1-Letter 3-Letter Amino Acid Y Tyr L-tyrosine G Gly L- 1 cine F Phe L
M Met L-methionine A Ala L-alanine S Ser L-serine I He L-isoleucine L Leu L-leucine T Thr L-threonine V Val L-valine P Pro L-proline K Lys L-lysine H His L-histidine 0 Gin L- lutamine E Glu L-glutamic acid W Trp L- tohan R Arg L-arginine D Asp L-as artic acid N Asn L-as ara ine C Cys L-cysteine [0046] It should be noted that all amino acid residue sequences are represented herein by formulae whose left to right orientation is in the conventional direction of amino-terminus to carboxy-terminus.
[0047] Except when noted, the terms "subject" or "patient" are used interchangeably and refer to mammals such as human patients and non-human primates, as well as experimental animals such as rabbits, rats, and mice, and other animals.
Accordingly, the term "subject" or "patient" as used herein means any mammalian patient or subject to which the compositions of the invention can be administered. In an exemplary embodiment of the present invention, to identify subject patients for treatment with a pharmaceutical composition comprising one or more antimicrobial peptides and/or proteins according to the methods of the invention, accepted screening methods are employed to determine the status of an existing disease or condition in a subject or risk factors associated with a targeted or suspected disease or condition. These screening methods include, for example, examinations to determine whether a subject is suffering from a microbial-based disease or disorder. These and other routine methods allow the clinician to select subjects in need of therapy.

B. PEPTIDES
[0048] The invention provides an isolated antimicrobial peptide. Exemplary peptides of the invention have an amino acid sequence including those listed in Table 1, and analogs, derivatives, amidated variations and conservative variations thereof, wherein the peptides have antimicrobial activity. The peptides of the invention include SEQ ID
NOS: 2-2166, as well as the broader groups of peptides having hydrophilic and hydrophobic substitutions, and conservative variations thereof.
[0049] "Isolated" when used in reference to a peptide, refers to a peptide substantially free of proteins, lipids, nucleic acids, for example, with which it can be naturally associated. Those of skill in the art can make similar substitutions to achieve peptides with greater antimicrobial activity and a broader host range. For example, the invention includes the peptides depicted in SEQ ID NOS: 1-2166, as well as analogs or derivatives thereof, as long as the bioactivity (e.g., antimicrobial) of the peptide remains.
Minor modifications of the primary amino acid sequence of the peptides of the invention may result in peptides that have substantially equivalent activity as compared to the specific peptides described herein. Such modifications may be deliberate, as by site-directed mutagenesis, or may be spontaneous. All of the peptides produced by these modifications are included herein as long as the biological activity of the original peptide still exists.
[0050] Further, deletion of one or more amino acids can also result in a modification of the structure of the resultant molecule without significantly altering its biological activity. This can lead to the development of a smaller active molecule that would also have utility. For example, amino or carboxy terminal amino acids that may not be required for biological activity of the particular peptide can be removed.
Peptides of the invention include any analog, homolog, mutant, isomer or derivative of the peptides disclosed in the present invention, so long as the bioactivity as described herein remains.
All peptides were synthesized using L amino acids, however, all D forms of the peptides can be synthetically produced. In addition, C-terminal derivatives can be produced, such as C-terminal methyl esters and C-terminal amidates, in order to increase the antimicrobial activity of a peptide of the invention. The peptide can be synthesized such that the sequence is reversed whereby the last amino acid in the sequence becomes the first amino acid, and the penultimate amino acid becomes the second amino acid, and so on.
It is well known that such reversed peptides usually have similar antimicrobial activities to the original sequence.
[0051] In certain embodiments, the peptides of the invention include peptide analogs and peptide mimetics. Indeed, the peptides of the invention include peptides having any of a variety of different modifications, including those described herein.
[0052] Peptide analogs of the invention are generally designed and produced by chemical modifications of a lead peptide, including, e.g., any of the particular peptides described herein, such as any of the following sequences disclosed in the tables. The present invention clearly establishes that these peptides in their entirety and derivatives created by modifying any side chains of the constituent amino acids have the ability to inhibit, prevent, or destroy the growth or proliferation of microbes such as bacteria, fungi, viruses, parasites or the like. The present invention further encompasses polypeptides up to about 50 amino acids in length that include the amino acid sequences and functional variants or peptide mimetics of the sequences described herein.
[0053] In another embodiment, a peptide of the present invention is a pseudopeptide. Pseudopeptides or amide bond surrogates refers to peptides containing chemical modifications of some (or all) of the peptide bonds. The introduction of amide bond surrogates not only decreases peptide degradation but also may significantly modify some of the biochemical properties of the peptides, particularly the conformational flexibility and hydrophobicity.
[0054] To improve or alter the characteristics of polypeptides of the present invention, protein engineering can be employed. Recombinant DNA technology known to those skilled in the art can be used to create novel mutant proteins or muteins including single or multiple amino acid substitutions, deletions, additions, or fusion proteins. Such modified polypeptides can show, e.g., increased/decreased biological activity or increased/decreased stability. In addition, they can be purified in higher yields and show better solubility than the corresponding natural polypeptide, at least under certain purification and storage conditions. Further, the polypeptides of the present invention can be produced as multimers including dimers, trimers and tetramers.
Multimerization can be facilitated by linkers, introduction of cysteines to permit creation of interchain disulphide bonds, or recombinantly though heterologous polypeptides such as Fc regions.

[0055] It is known in the art that one or more amino acids can be deleted from the N-terminus or C-terminus without substantial loss of biological function.
See, e.g., Ron et al., Biol Chem. 268: 2984-2988, 1993. Accordingly, the present invention provides polypeptides having one or more residues deleted from the amino terminus.
Similarly, many examples of biologically functional C-terminal deletion mutants are known (see, e.g., Dobeli et al., J. Biotechnology 7: 199-216, 1988). Accordingly, the present invention provides polypeptides having one or more residues deleted from the carboxy terminus.
The invention also provides polypeptides having one or more amino acids deleted from both the amino and the carboxyl termini as described below.

[0056] Other mutants in addition to N- and C-terminal deletion forms of the protein discussed above are included in the present invention. Thus, the invention further includes variations of the polypeptides which show substantial chaperone polypeptide activity. Such mutants include deletions, insertions, inversions, repeats, and substitutions selected according to general rules known in the art so as to have little effect on activity.
[0057] There are two main approaches for studying the tolerance of an amino acid sequence to change, see, Bowie et al., Science 247: 1306-1310, 1994. The first method relies on the process of evolution, in which mutations are either accepted or rejected by natural selection. The second approach uses genetic engineering to introduce amino acid changes at specific positions of a cloned gene and selections or screens to identify sequences that maintain functionality. These studies have revealed that proteins are surprisingly tolerant of amino acid substitutions.

[0058] Typically seen as conservative substitutions are the replacements, one for another, among the aliphatic amino acids Ala, Val, Leu and Phe; interchange of the hydroxyl residues Ser and Thr, exchange of the acidic residues Asp and Glu, substitution between the amide residues Asn and Gln, exchange of the basic residues Lys and Arg and replacements among the aromatic residues Phe, Tyr. Thus, the polypeptide of the present invention can be, for example: (i) one in which one or more of the amino acid residues are substituted with a conserved or non-conserved amino acid residue (preferably a conserved amino acid residue) and such substituted amino acid residue can or cannot be one encoded by the genetic code; or (ii) one in which one or more of the amino acid residues includes a substituent group; or (iii) one in which the polypeptide is fused with another compound, such as a compound to increase the half-life of the polypeptide (for example, polyethylene glycol); or (iv) one in which the additional amino acids are fused to the above form of the polypeptide, such as an IgG Fc fusion region peptide or leader or secretory sequence or a sequence which is employed for purification of the above form of the polypeptide or a pro-protein sequence.
[0059] Thus, the polypeptides of the present invention can include one or more amino acid substitutions, deletions, or additions, either from natural mutations or human manipulation. As indicated, changes are preferably of a minor nature, such as conservative amino acid substitutions that do not significantly affect the folding or activity of the protein. The following groups of amino acids represent equivalent changes: (1) Ala, Pro, Gly, Glu, Asp, Gln, Asn, Ser, Thr; (2) Cys, Ser, Tyr, Thr; (3) Val, Ile, Leu, Met, Ala, Phe;
(4) Lys, Arg, His; (5) Phe, Tyr, Trp, His.
[0060] Furthermore, polypeptides of the present invention can include one or more amino acid substitutions that mimic modified amino acids. An example of this type of substitution includes replacing amino acids that are capable of being phosphorylated (e.g., serine, threonine, or tyrosine) with a negatively charged amino acid that resembles the negative charge of the phosphorylated amino acid (e.g., aspartic acid or glutamic acid).
Also included is substitution of amino acids that are capable of being modified by hydrophobic groups (e.g., arginine) with amino acids carrying bulky hydrophobic side chains, such as tryptophan or phenylalanine. Therefore, a specific embodiment of the invention includes polypeptides that include one or more amino acid substitutions that mimic modified amino acids at positions where amino acids that are capable of being modified are normally positioned. Further included are polypeptides where any subset of modifiable amino acids is substituted. For example, a polypeptide that includes three serine residues can be substituted at any one, any two, or all three of said serines.
Furthermore, any polypeptide amino acid capable of being modified can be excluded from substitution with a modification-mimicking amino acid.
[0061] The present invention is fiuther directed to fragments of the polypeptides of the present invention. More specifically, the present invention embodies purified, isolated, and recombinant polypeptides comprising at least any one integer between 6 and 504 (or the length of the polypeptides amino acid residues minus 1 if the length is less than 1000) of consecutive amino acid residues. Preferably, the fragments are at least 6, preferably at least 8 to 10, more preferably 12, 15, 20, 25, 30, 35, 40, 50 or more consecutive amino acids of a polypeptide of the present invention.
[0062] The present invention also provides for the exclusion of any species of polypeptide fragments of the present invention specified by 5' and 3' positions or sub-genuses of polypeptides specified by size in amino acids as described above.
Any number of fragments specified by 5' and 3' positions or by size in amino acids, as described above, can be excluded.

[0063] In addition, it should be understood that in certain embodiments, the peptides of the present invention include two or more modifications, including, but not limited to those described herein. By taking into the account the features of the peptide drugs on the market or under current development, it is clear that most of the peptides successfully stabilized against proteolysis consist of a mixture of several types of the above described modifications. This conclusion is understood in the light of the knowledge that many different enzymes are implicated in peptide degradation.

C. PEPTIDES, PEPTIDE VARIANTS, AND PEPTIDE MIMETICS
[0064] "Polypeptide," "peptide" and "protein" are used interchangeably herein to refer to a polymer of amino acid residues. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymer. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but which functions in a manner similar to a naturally occurring amino acid.
Non-natural residues are well described in the scientific and patent literature; a few exemplary non-natural compositions useful as mimetics of natural amino acid residues and guidelines are described below. Mimetics of aromatic amino acids can be generated by replacing by, e.g., D- or L-naphylalanine; D- or L-phenylglycine; D- or L-2 thieneylalanine; D- or L-1, -2,3-, or 4-pyreneylalanine; D- or L-3 thieneylalanine; D- or L-(2-pyridinyl)-alanine; D- or L-(3-pyridinyl)-alanine; D- or L-(2-pyrazinyl)-alanine; D- or L-(4-isopropyl)-phenylglycine; D-(trifluoromethyl)-phenylglycine; D-(trifluoromethyl)-phenylalanine; D-p-fluoro-phenylalanine; D- or L-p-biphenylphenylalanine; K-or L-p-methoxy-biphenylphenylalanine; D- or L-2-indole(alkyl)alanines; and, D- or L-alkylainines, where alkyl can be substituted or unsubstituted methyl, ethyl, propyl, hexyl, butyl, pentyl, isopropyl, iso-butyl, sec-isotyl, iso-pentyl, or a non-acidic amino acids.

Aromatic rings of a non-natural amino acid include, e.g., thiazolyl, thiophenyl, pyrazolyl, benzimidazolyl, naphthyl, furanyl, pyrrolyl, and pyridyl aromatic rings.
[0065] "Peptide" as used herein includes peptides that are conservative variations of those peptides specifically exemplified herein. "Conservative variation" as used herein denotes the replacement of an amino acid residue by another, biologically similar residue.
Examples of conservative variations include, but are not limited to, the substitution of one hydrophobic residue such as isoleucine, valine, leucine, alanine, cysteine, glycine, phenylalanine, proline, tryptophan, tyrosine, norleucine or methionine for another, or the substitution of one polar residue for another, such as the substitution of arginine for lysine, glutamic for aspartic acids, or glutamine for asparagine, and the like.
Neutral hydrophilic amino acids that can be substituted for one another include asparagine, glutamine, serine and threonine. The term "conservative variation" also includes the use of a substituted amino acid in place of an unsubstituted parent amino acid provided that antibodies raised to the substituted polypeptide also immunoreact with the unsubstituted polypeptide. Such conservative substitutions are within the definition of the classes of the peptides of the invention. "Cationic" as is used to refer to any peptide that possesses sufficient positively charged amino acids to have a pI (isoelectric point) greater than about 9Ø
[0066] The biological activity of the peptides can be determined by standard methods known to those of skill in the art, such as "minimal inhibitory concentration (MIC)" assay described in the present examples, whereby the lowest concentration at which no change in OD is observed for a given period of time is recorded as MIC.
[0067] The peptides and polypeptides of the invention, as defined above, include all "mimetic" and "peptidomimetic " forms. The terms "mimetic" and "peptidomimetic"
refer to a synthetic chemical compound that has substantially the same structural and/or functional characteristics of the polypeptides of the invention. The mimetic can be either entirely composed of synthetic, non-natural analogues of amino acids, or, is a chimeric molecule of partly natural peptide amino acids and partly non-natural analogs of amino acids. The mimetic can also incorporate any amount of natural amino acid conservative substitutions as long as such substitutions also do not substantially alter the mimetic's structure and/or activity. As with polypeptides of the invention which are conservative variants, routine experimentation will determine whether a mimetic is within the scope of the invention, i.e., that its structure and/or function is not substantially altered. Thus, a mimetic composition is within the scope of the invention if, when administered to or expressed in a cell, e.g., a polypeptide fragment of an animicrobial protein having antimicrobial activity.
[0068] Polypeptide mimetic compositions can contain any combination of non-natural structural components, which are typically from three structural groups: a) residue linkage groups other than the natural amide bond ("peptide bond") linkages; b) non-natural residues in place of naturally occurring amino acid residues; or c) residues which induce secondary structural mimicry, i.e., to induce or stabilize a secondary structure, e.g., a beta turn, gamma turn, beta sheet, alpha helix conformation, and the like.
For example, a polypeptide can be characterized as a mimetic when all or some of its residues are joined by chemical means other than natural peptide bonds. Individual peptidomimetic residues can be joined by peptide bonds, other chemical bonds or coupling means, such as, e.g., glutaraldehyde, N-hydroxysuccinimide esters, bifunctional maleimides, N,N'-dicyclohexylcarbodiimide (DCC) or N,N'-diisopropylcarbodiimide (DIC). Linking groups that can be an alternative to the traditional amide bond ("peptide bond") linkages include, e.g., ketomethylene (e.g., --C(=O)-CH2-for -C(=O)-NH--), aminomethylene (CH2-NH), ethylene, olefin (CH=CH), ether (CHa-O), thioether (CH2-S), tetrazole (CN4--), thiazole, retroamide, thioamide, or ester (see, e.g., Spatola, 1983, Chemistry and Biochemistry of Amino Acids, Peptides and Proteins 7: 267-357).
[0069] Mimetics of acidic amino acids can be generated by substitution by, e.g., non-carboxylate amino acids while maintaining a negative charge;
(phosphono)alanine;
sulfated threonine. Carboxyl side groups (e.g., aspartyl or glutamyl) can also be selectively modified by reaction with carbodiimides (R'-N-C-N-R') such as, e.g., 1-cyclohexyl-3(2-morpholin-yl-(4-ethyl) carbodiimide or 1-ethyl-3(4-azonia-4,4-dimetholpentyl) carbodiimide. Aspartyl or glutamyl can also be converted to asparaginyl and glutaminyl residues by reaction with ammonium ions.
[0070] Mimetics of basic amino acids can be generated by substitution with, e.g., (in addition to lysine and arginine) the amino acids ornithine, citrulline, guanidino-acetic acid, or (guanidino)alkyl-acetic acid, where alkyl is defined above. Nitrile derivative (e.g., containing the CN-moiety in place of COOH) can be substituted for asparagine or glutamine. Asparaginyl and glutaminyl residues can be deaminated to the corresponding aspartyl or glutamyl residues.
[0071] Arginine residue mimetics can be generated by reacting arginyl with, e.g., one or niore conventional reagents, including, e.g., phenylglyoxal, 2,3-butanedione, 1,2-cyclohexanedione, or ninhydrin, preferably under alkaline conditions. Tyrosine residue mimetics can be generated by reacting tyrosyl with, e.g., aromatic diazonium compounds or tetranitromethane. N-acetylimidizol and tetranitromethane can be used to form 0-acetyl tyrosyl species and 3-nitro derivatives, respectively. Cysteine residue mimetics can be generated by reacting cysteinyl residues with, e.g., alpha-haloacetates such as 2-chloroacetic acid or chloroacetamide and corresponding amines; to give carboxymethyl or carboxyamidomethyl derivatives. Cysteine residue mimetics can also be generated by reacting cysteinyl residues with, e.g., bromo-trifluoroacetone, alpha-bromo-beta-(5-imidozoyl) propionic acid; chloroacetyl phosphate, N-alkylmaleimides, 3-nitro-2-pyridyl disulfide; methyl 2-pyridyl disulfide; p-chloromercuribenzoate; 2-chloromercuri-4 nitrophenol; or, chloro-7-nitrobenzo-oxa-1,3-diazole. Lysine mimetics can be generated (and amino terminal residues can be altered) by reacting lysinyl with, e.g., succinic or other carboxylic acid anhydrides. Lysine and other alpha-amino-containing residue mimetics can also be generated by reaction with imidoesters, such as methyl picolinimidate, pyridoxal phosphate, pyridoxal, chloroborohydride, trinitrobenzenesulfonic acid, 0-methylisourea, 2,4, pentanedione, and transamidase-catalyzed reactions with glyoxylate. Mimetics of methionine can be generated by reaction with, e.g., methionine sulfoxide. Mimetics of proline include, e.g., pipecolic acid, thiazolidine carboxylic acid, 3- or 4-hydroxy proline, dehydroproline, 3- or 4-methylproline, or 3,3,-dimethylproline. Histidine residue mimetics can be generated by reacting histidyl with, e.g., diethylprocarbonate or para-bromophenacyl bromide. Other mimetics include, e.g., those generated by hydroxylation of proline and lysine;
phosphorylation of the hydroxyl groups of seryl or threonyl residues;
methylation of the alpha-amino groups of lysine, arginine and histidine; acetylation of the N-terminal amine;
methylation of main chain amide residues or substitution with N-methyl amino acids; or amidation of C-terminal carboxyl groups.
[0072] A component of a polypeptide of the invention can also be replaced by an amino acid (or peptidomimetic residue) of the opposite chirality. Thus, any amino acid naturally occurring in the L-configuration (which can also be referred to as the R or S, depending upon the structure of the chemical entity) can be replaced with the amino acid of the same chemical structural type or a peptidomimetic, but of the opposite chirality, referred to as the D-amino acid, but which can additionally be referred to as the R- or S-form [0073] The invention also provides polypeptides that are "substantially identical"
to an exemplary polypeptide of the invention. A "substantially identical"
amino acid sequence is a sequence that differs from a reference sequence by one or more conservative or non-conservative amino acid substitutions, deletions, or insertions, particularly when such a substitution occurs at a site that is not the active site of the molecule, and provided that the polypeptide essentially retains its functional properties. A
conservative amino acid substitution, for example, substitutes one amino acid for another of the same class (e.g., substitution of one hydrophobic amino acid, such as isoleucine, valine, leucine, or methionine, for another, or substitution of one polar amino acid for another, such as substitution of arginine for lysine, glutamic acid for aspartic acid or glutamine for asparagine). One or more amino acids can be deleted, for example, from an antimicrobial polypeptide having antimicrobial activity of the invention, resulting in modification of the structure of the polypeptide, without significantly altering its biological activity. For example, amino- or carboxyl-terminal, or internal, amino acids that are not required for antimicrobial activity can be removed.
[0074] The skilled artisan will recognize that individual synthetic residues and polypeptides incorporating these mimetics can be synthesized using a variety of procedures and methodologies, which are well described in the scientific and patent literature, e.g., Organic Syntheses Collective Volumes, Gilman, et al. (Eds) John Wiley &
Sons, Inc., NY. Peptides and peptide mimetics of the invention can also be synthesized using combinatorial methodologies. Various techniques for generation of peptide and peptidomimetic libraries are well known, and include, e.g., multipin, tea bag, and split-couple-mix techniques; see, e.g., al-Obeidi, Mol. Biotechnol. 9: 205-223, 1998; Hruby, Curr. Opin. Clzem. Biol. 1: 114-119, 1997; Ostergaard, Mol. Divers. 3: 17-27, 1997;
Ostresh, Metlaods Enzymol. 267: 220-234, 1996. Modified peptides of the invention can be further produced by chemical modification methods, see, e.g., Belousov, Nucleic Acids Res. 25: 3440-3444, 1997; Frenkel, Free Radic. Biol. Med. 19: 373-380, 1995;
Blommers, Biochemistry 33: 7886-7896, 1994.
[0075] Polypeptides and peptides of the invention can be isolated from natural sources, be synthetic, or be recombinantly generated polypeptides. Peptides and proteins can be recombinantly expressed in vitro or in vivo. The peptides and polypeptides of the invention can be made and isolated using any method known in the art.
Polypeptide and peptides of the invention can also be synthesized, whole or in part, using chemical methods well known in the art. See e.g., Caruthers, Nucleic Acids Res. Symp.
Ser. 215-223, 1980; Horn, Nucleic Acids Res. Symp. Ser. 225-232, 1980; Banga, 1995, Therapeutic Peptides and Proteins, Formulation, Processing and Delivery Systems. For example, peptide synthesis can be performed using various solid-phase techniques (see e.g., Roberge, Science 269: 202, 1995; Merrifield, Methods Enzymol. 289: 3-13, 1997) and automated synthesis can be achieved, e.g., using the ABI 43 1A Peptide Synthesizer (Perkin Elmer) in accordance with the instructions provided by the manufacturer.
[0076] Peptides of the invention can be synthesized by such commonly used methods as t-BOC or FMOC protection of alpha-amino groups. Both methods involve stepwise syntheses whereby a single amino acid is added at each step starting from the C
terminus of the peptide (See, Coligan et al., Current Protocols in Immunology, Wiley Interscience, 1991, Unit 9). Peptides of the invention can also be synthesized by the well known solid phase peptide synthesis methods described in Merrifield, J. Am.
Chem. Soc.
85: 2149, 1962, and Stewart and Young, 1969, Solid Phase Peptides Syntlaesis 27-62, using a copoly(styrene-divinylbenzene) containing 0.1-1.0 mMol amines/g polymer. On completion of chemical synthesis, the peptides can be deprotected and cleaved from the polymer by treatment with liquid HF-10% anisole for about 1/4-1 hours at 0 C.
After evaporation of the reagents, the peptides are extracted from the polymer with 1% acetic acid solution which is then lyophilized to yield the crude material. This can normally be purified by such techniques as gel filtration on Sephadex G-15 using 5% acetic acid as a solvent. Lyophilization of appropriate fractions of the column will yield the homogeneous peptide or peptide derivatives, which can then be characterized by such standard techniques as amino acid analysis, thin layer chromatography, high performance liquid chromatography, ultraviolet absorption spectroscopy, molar rotation, solubility, and quantitated by the solid phase Edman degradation.

[0077] Analogs, polypeptide fragment of antimicrobial protein having antimicrobial activity, are generally designed and produced by chemical modifications of a lead peptide, including, e.g., any of the particular peptides described herein, such as any of the sequences including SEQ ID NOS:1-2166.

[0078] The terms "identical" or percent "identity", in the context of two or more nucleic acids or polypeptide sequences, refers to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity over a specified region (e.g., nucleotide sequence encoding an antibody described herein or amino acid sequence of an antibody described herein), when compared and aligned for maximum correspondence over a comparison window or designated region) as measured using a BLAST or BLAST 2.0 sequence comparison algorithms with default parameters described below, or by manual alignment and visual inspection. Such sequences are then said to be "substantially identical." This term also refers to, or can be applied to, the compliment of a test sequence. The term also includes sequences that have deletions and/or additions, as well as those that have substitutions. As described below, the preferred algorithms can account for gaps and the like. Preferably, identity exists over a region that is at least about 25 amino acids or nucleotides in length, or more preferably over a region that is 50-100 amino acids or nucleotides in length.
[0079] For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Preferably, default program parameters can be used, or alternative parameters can be designated. The sequence comparison algorithm then calculates the percent sequence identities for the test sequences relative to the reference sequence, based on the program parameters.
[0080] A "comparison window", as used herein, includes reference to a segment of any one of the number of contiguous positions selected from the group consisting of from 20 to 600, usually about 50 to about 200, more usually about 100 to about 150 in which a sequence can be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned. Methods of alignment of sequences for comparison are well-known in the art. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith &
Waterman, Adv. Appl. Math. 2: 482, 1981, by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48: 443, 1970, by the search for similarity method of Pearson & Lipman, Proc. Nat'l. Acad. Sci. USA 85: 2444, 1988, by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI), or by manual alignment and visual inspection (see, e.g., Ausubel et al., 1995 supplement, Current Protocols in Molecular Biology).
[0081] Programs for searching for alignments are well known in the art, e.g., BLAST and the like. For example, if the target species is human, a source of such amino acid sequences or gene sequences (germline or rearranged antibody sequences) can be found in any suitable reference database such as Genbank, the NCBI protein databank (http://ncbi.nlm.nih.gov/BLAST/), VBASE, a database of human antibody genes (http://www.mrc-cpe.cam.ac.uk/imt-doc), and the Kabat database of immunoglobulins (http://www.immuno.bme.nwu.edu) or translated products thereof. If the alignments are done based on the nucleotide sequences, then the selected genes should be analyzed to determine which genes of that subset have the closest amino acid homology to the originating species antibody. It is contemplated that amino acid sequences or gene sequences which approach a higher degree homology as compared to other sequences in the database can be utilized and manipulated in accordance with the procedures described herein. Moreover, amino acid sequences or genes which have lesser homology can be utilized when they encode products which, when manipulated and selected in accordance with the procedures described herein, exhibit specificity for the predetermined target antigen. In certain embodiments, an acceptable range of homology is greater than about 50%. It should be understood that target species can be other than human.
[0082] A preferred example of algorithm that is suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al., Nuc. Acids Res. 25: 3389-3402, 1977 and Altschul et al., J. Mol. Biol. 215: 403-410, 1990, respectively. BLAST and BLAST 2.0 are used, with the parameters described herein, to determine percent sequence identity for the nucleic acids and proteins of the invention. Software for performing BLAST
analyses is publicly available through the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/). This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold. These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are extended in both directions along each sequence for as far as the cumulative alignment score can be increased.
Cumulative scores are calculated using, for nucleotide sequences, the parameters M
(reward score for a pair of matching residues; always > 0) and N (penalty score for mismatching residues;
always < 0). For amino acid sequences, a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value;
the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached.
The BLAST
algorithm parameters W, T, and X determine the sensitivity and speed of the alignment.
The BLASTN program (for nucleotide sequences) uses as defaults a wordlength (W) of 11, an expectation (E) of 10, M=5, N=-4 and a comparison of both strands. For amino acid sequences, the BLASTP program uses as defaults a wordlength of 3, and expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff & Henikoff, Proc.lVatl.
Acad.
Sci. USA 89: 10915, 1989) alignments (B) of 50, expectation (E) of 10, M=5, N=-4, and a comparison of both strands.

D. POLYPEPTIDES AND FUNCTIONAL VARIANTS THEREOF
[0083] "Polypeptide" includes proteins, fusion proteins, oligopeptides and polypeptide derivatives, with the exception that peptidomimetics are considered to be small molecules herein.
[0084] A "protein" is a molecule having a sequence of amino acids that are linked to each other in a linear molecule by peptide bonds. The term protein refers to a polypeptide that is isolated from a natural source, or produced from an isolated cDNA
using recombinant DNA technology; and has a sequence of amino acids having a length of at least about 200 amino acids.
[0085] A "fusion protein" is a type of recombinant protein that has an amino acid sequence that results from the linkage of the amino acid sequences of two or more normally separate polypeptides.
[0086] A "protein fragment" is a proteolytic fragment of a larger polypeptide, which may be a protein or a fusion protein. A proteolytic fragment may be prepared by in vivo or in vitro proteolytic cleavage of a larger polypeptide, and is generally too large to be prepared by chemical synthesis. Proteolytic fragments have amino acid sequences having a length from about 200 to about 1,000 amino acids.

[0087] An "oligopeptide" or "peptide" is a polypeptide having a short amino acid sequence (i.e., 2 to about 200 amino acids). An oligopeptide is generally prepared by chemical synthesis.

[0088] Although oligopeptides and protein fragments may be otherwise prepared, it is possible to use recombinant DNA technology and/or in vitro biochemical manipulations. For example, a nucleic acid encoding an amino acid sequence may be prepared and used as a template for in vitro transcription/translation reactions. In such reactions, an exogenous nucleic acid encoding a preselected polypeptide is introduced into a mixture that is essentially depleted of exogenous nucleic acids that contains all of the cellular components required for transcription and translation. One or more radiolabeled amino acids are added before or with the exogenous DNA, and transcription and translation are allowed to proceed. Because the only nucleic acid present in the reaction mix is the exogenous nucleic acid added to the reaction, only polypeptides encoded thereby are produced, and incorporate the radiolabeled amino acid(s). In this manner, polypeptides encoded by a preselected exogenous nucleic acid are radiolabeled.
Although other proteins are present in the reaction mix, the preselected polypeptide is the only one that is produced in the presence of the radiolabeled amino acids and is thus uniquely labeled.

[0089] As is explained in detail below, "polypeptide derivatives" include without limitation mutant polypeptides, chemically modified polypeptides, and peptidomimetics.
[0090] The polypeptides of this invention, including the analogs and other modified variants, may generally be prepared following known techniques.
Preferably, synthetic production of the polypeptide of the invention may be according to the solid phase synthetic method. For example, the solid phase synthesis is well understood and is a common method for preparation of polypeptides, as are a variety of modifications of that technique. Merrifield, J. Am. Chem. Soc., 85: 2149, 1964; Stewart and Young, 1984, Solid Phase polypeptide Synthesis; Bodansky and Bodanszky, 1984, The Practice of polypeptide Synthesis; Atherton and Sheppard, 1989, Solid Phase polypeptide Synthesis: A
Practical Approach. See, also, the specific method described in Example 1 below.
[0091] Alternatively, polypeptides of this invention may be prepared in recombinant systems using polynucleotide sequences encoding the polypeptides.
[0092] A "variant" or "functional variant" of a polypeptide is a compound that is not, by definition, a polypeptide, i.e., it contains at least one chemical linkage that is not a peptide bond. Thus, polypeptide derivatives include without limitation proteins that naturally undergo post-translational modifications such as, e.g., glycosylation. It is understood that a polypeptide of the invention may contain more than one of the following modifications within the same polypeptide. Preferred polypeptide derivatives retain a desirable attribute, which may be biological activity; more preferably, a polypeptide derivative is enhanced with regard to one or more desirable attributes, or has one or more desirable attributes not found in the parent polypeptide. Although they are described in this section, peptidomimetics are taken as small molecules in the present disclosure.
[0093] A polypeptide having an amino acid sequence identical to that found in a protein prepared from a natural source is a "wild type" polypeptide.
Functional variants of polypeptides can be prepared by chemical synthesis, including without limitation combinatorial synthesis.
[0094] Functional variants of polypeptides larger than oligopeptides can be prepared using recombinant DNA technology by altering the nucleotide sequence of a nucleic acid encoding a polypeptide. Although some alterations in the nucleotide sequence will not alter the amino acid sequence of the polypeptide encoded thereby ("silent"
mutations), many will result in a polypeptide having an altered amino acid sequence that is altered relative to the parent sequence. Such altered amino acid sequences may comprise substitutions, deletions and additions of amino acids, with the proviso that such amino acids are naturally occurring amino acids.
[0095] Thus, subjecting a nucleic acid that encodes a polypeptide to mutagenesis is one technique that can be used to prepare Functional variants of polypeptides, particularly ones having substitutions of amino acids but no deletions or insertions thereof.
A variety of mutagenic techniques are known that can be used in vitro or in vivo including without limitation chemical mutagenesis and PCR-mediated mutagenesis. Such mutagenesis may be randomly targeted (i.e., mutations may occur anywhere within the nucleic acid) or directed to a section of the nucleic acid that encodes a stretch of amino acids of particular interest. Using such techniques, it is possible to prepare randomized, combinatorial or focused compound libraries, pools and mixtures.
[0096] Polypeptides having deletions or insertions of naturally occurring amino acids may be synthetic oligopeptides that result from the chemical synthesis of amino acid sequences that are based on the amino acid sequence of a parent polypeptide but which have one or more amino acids inserted or deleted relative to the sequence of the parent polypeptide. Insertions and deletions of amino acid residues in polypeptides having longer amino acid sequences may be prepared by directed mutagenesis.
[0097] As contemplated by this invention, "polypeptide" includes those having one or more chemical modification relative to another polypeptide, i.e., chemically modified polypeptides. The polypeptide from which a chemically modified polypeptide is derived may be a wild type protein, a functional variant protein or a functional variant polypeptide, or polypeptide fragments thereof; an antibody or other polypeptide ligand according to the invention including without limitation single-chain antibodies, crystalline proteins and polypeptide derivatives thereof; or polypeptide ligands prepared according to the disclosure. Preferably, the chemical modification(s) confer(s) or improve(s) desirable attributes of the polypeptide but does not substantially alter or compromise the biological activity thereof. Desirable attributes include but are limited to increased shelf-life;
enhanced serum or other in vivo stability; resistance to proteases; and the like. Such modifications include by way of non-limiting example N-terminal acetylation, glycosylation, and biotinylation.
[0098] An effective approach to confer resistance to peptidases acting on the N-terminal or C-terminal residues of a polypeptide is to add chemical groups at the polypeptide termini, such that the modified polypeptide is no longer a substrate for the peptidase. One such chemical modification is glycosylation of the polypeptides at either or botli termini. Certain chemical modifications, in particular N-terminal glycosylation, have been shown to increase the stability of polypeptides in human serum. Powell et al., Phanna. Res. 10: 1268-1273, 1993. Other chemical modifications which enhance serum stability include, but are not limited to, the addition of an N-terminal alkyl group, consisting of a lower alkyl of from 1 to 20 carbons, such as an acetyl group, and/or the addition of a C-terminal amide or substituted amide group.
[0099] The presence of an N-terminal D-amino acid increases the serum stability of a polypeptide that otherwise contains L-amino acids, because exopeptidases acting on the N-terminal residue cannot utilize a D-amino acid as a substrate.
Similarly, the presence of a C-terminal D-amino acid also stabilizes a polypeptide, because serum exopeptidases acting on the C-terminal residue cannot utilize a D-amino acid as a substrate.
With the exception of these terminal modifications, the amino acid sequences of polypeptides with N-terminal and/or C-terminal D-amino acids are usually identical to the sequences of the parent L-amino acid polypeptide.

[0100] Substitution of unnatural amino acids for natural amino acids in a subsequence of a polypeptide can confer or enhance desirable attributes including biological activity. Such a substitution can, for example, confer resistance to proteolysis by exopeptidases acting on the N-terminus. The synthesis of polypeptides with unnatural amino acids is routine and known in the art (see, for example, Coller, et al.
1993, cited above).
[0101] Different host cells will contain different post-translational modification mechanisms that may provide particular types of post-translational modification of a fusion protein if the amino acid sequences required for such modifications is present in the fusion protein. A large number (about 100) of post-translational modifications have been described, a few of which are discussed herein. One skilled in the art will be able to choose appropriate host cells, and design chimeric genes that encode protein members comprising the amino acid sequence needed for a particular type of modification.
[0102] Glycosylation is one type of post-translational chemical modification that occurs in many eukaryotic systems, and may influence the activity, stability, pharmacogenetics, immunogenicity and/or antigenicity of proteins. However, specific amino acids must be present at such sites to recruit the appropriate glycosylation machinery, and not all host cells have the appropriate molecular machinery.
Saccharomyces cerevisieae and Pichia pastoris provide for the production of glycosylated proteins, as do expression systems that utilize insect cells, although the pattern of glyscoylation may vary depending on which host cells are used to produce the fusion protein.
[0103] Another type of post-translation modification is the phosphorylation of a free hydroxyl group of the side chain of one or more Ser, Thr or Tyr residues, Protein kinases catalyze such reactions. Phosphorylation is often reversible due to the action of a protein phosphatase, an enzyme that catalyzes the dephosphorylation of amino acid residues.
[0104] Differences in the chemical structure of amino terminal residues result from different host cells, each of which may have a different chemical version of the methionine residue encoded by a start codon, and these will result in amino termini with different chemical modifications.
[0105] For example, many or most bacterial proteins are synthesized with an amino terminal amino acid that is a modified form of methionine, i.e., N-formyl-methionine (fMet). Although the statement is often made that all bacterial proteins are synthesized with an fMet initiator amino acid; although this may be true for E. coli, recent studies have shown that it is not true in the case of other bacteria such as Pseudomonas aeruginosa. Newton et al., J. Biol. Chem. 274: 22143-22146, 1999. In any event, in E.
coli, the formyl group of fMet is usually enzymatically removed after translation to yield an amino terminal methionine residue, although the entire fMet residue is sometimes removed (see Hershey, 1987, Escherichia coli and Salmonella Typhirnurium:
Cellular and Molecular Biology 1: 613-647, and references cited therein.). E. coli mutants that lack the enzymes (such as, e.g., formylase) that catalyze such post-translational modifications will produce proteins having an amino terminal fMet residue (Guillon et al., J.
Bacteriol. 174:
4294-4301, 1992).
[0106] In eukaryotes, acetylation of the initiator methionine residue, or the penultimate residue if the initiator methionine has been removed, typically occurs co- or post-translationally. The acetylation reactions are catalyzed by N-tenninal acetyltransferases (NATs, a.k.a. N-alpha-acetyltransferases), whereas removal of the initiator methionine residue is catalyzed by methionine aminopeptidases (for reviews, see Bradshaw et al., Trends Biochem. Sci. 23: 263-267, 1998; and Driessen et al., CRC Crit.
Rev. Biochem. 18: 281-325, 1985). Amino terminally acetylated proteins are said to be "N-acetylated," "N alpha acetylated" or simply "acetylated."
[0107] Another post-translational process that occurs in eukaryotes is the alpha-amidation of the carboxy terminus. For reviews, see Eipper et al., Annu. Rev.
Physiol. 50:
333-344, 1988, and Bradbury et al., Lung Cancer 14: 239-251, 1996. About 50%
of known endocrine and neuroendocrine peptide hormones are alpha-amidated (Treston et al., Cell Growth Differ. 4: 911-920, 1993). In most cases, carboxy alpha-amidation is required to activate these peptide hormones.

E. POLYPEPTIDE MIMETIC
[0108] In general, a polypeptide mimetic ("peptidomimetic") is a molecule that mimics the biological activity of a polypeptide but is no longer peptidic in chemical nature. By strict definition, a peptidomimetic is a molecule that contains no peptide bonds (that is, amide bonds between amino acids). However, the term peptidomimetic is sometimes used to describe molecules that are no longer completely peptidic in nature, such as pseudo-peptides, semi-peptides and peptoids. Examples of some peptidomimetics by the broader definition (where part of a polypeptide is replaced by a structure lacking peptide bonds) are described below. Whether completely or partially non-peptide, peptidomimetics according to this invention provide a spatial arrangement of reactive chemical moieties that closely resembles the three-dimensional arrangement of active groups in the polypeptide on which the peptidomimetic is based. As a result of this similar active-site geometry, the peptidomimetic has effects on biological systems that are similar to the biological activity of the polypeptide.
[0109] There are several potential advantages for using a mimetic of a given polypeptide rather than the polypeptide itself. For example, polypeptides may exhibit two undesirable attributes, i.e., poor bioavailability and short duration of action.
Peptidomimetics are often small enough to be both orally active and to have a long duration of action. There are also problems associated with stability, storage and immunoreactivity for polypeptides that are not experienced with peptidomimetics.
[0110] Candidate, lead and other polypeptides having a desired biological activity can be used in the development of peptidomimetics with similar biological activities. Techniques of developing peptidomimetics from polypeptides are known.
Peptide bonds can be replaced by non-peptide bonds that allow the peptidomimetic to adopt a similar structure, and therefore biological activity, to the original polypeptide.
Further modifications can also be made by replacing chemical groups of the amino acids with other chemical groups of similar structure. The development of peptidomimetics can be aided by determining the tertiary structure of the original polypeptide, either free or bound to a ligand, by NMR spectroscopy, crystallography and/or computer-aided molecular modeling. These techniques aid in the development of novel compositions of higher potency and/or greater bioavailability and/or greater stability than the original polypeptide (Dean, BioEssays 16: 683-687, 1994; Cohen and Shatzmiller, J. Mol.
Graph.
11: 166-173, 1993; Wiley and Rich, Med. Res. Rev. 13: 327-384, 1993; Moore, Trends Pharmacol. Sci. 15: 124-129, 1994; Hruby, Biopolymers 33: 1073-1082, 1993;
Bugg et al., Sci. Am. 269: 92-98, 1993, all incorporated herein by reference].
[0111] Thus, through use of the methods described above, the present invention provides compounds exhibiting enhanced therapeutic activity in comparison to the polypeptides described above. The peptidomimetic compounds obtained by the above methods, having the biological activity of the above named polypeptides and similar three-dimensional structure, are encompassed by this invention. It will be readily apparent to one skilled in the art that a peptidomimetic can be generated from any of the modified polypeptides described in the previous section or from a polypeptide bearing more than one of the modifications described from the previous section. It will furthermore be apparent that the peptidomimetics of this invention can be further used for the development of even more potent non-peptidic compounds, in addition to their utility as therapeutic compounds.

[0112] Specific examples of peptidomimetics derived from the polypeptides described in the previous section are presented below. These examples are illustrative and not limiting in terms of the other or additional modifications.
[0113] Proteases act on peptide bonds. It therefore follows that substitution of peptide bonds by pseudopeptide bonds confers resistance to proteolysis. A
number of pseudopeptide bonds have been described that in general do not affect polypeptide structure and biological activity. The reduced isosteric pseudopeptide bond is a suitable pseudopeptide bond that is known to enhance stability to enzymatic cleavage with no or little loss of biological activity (Couder et al., Int. J. Polypeptide Protein Res. 41: 181-184, 1993, incorporated herein by reference). Thus, the amino acid sequences of these compounds may be identical to the sequences of their parent L-amino acid polypeptides, except that one or more of the peptide bonds are replaced by an isosteric pseudopeptide bond. Preferably the most N-terminal peptide bond is substituted, since such a substitution would confer resistance to proteolysis by exopeptidases acting on the N-terminus.
[0114] To confer resistance to proteolysis, peptide bonds may also be substituted by retro-inverso pseudopeptide bonds (Dalpozzo et al., Int. J. Polypeptide Protein Res. 41:
561-566, incorporated herein by reference). According to this modification, the amino acid sequences of the compounds may be identical to the sequences of their L-amino acid parent polypeptides, except that one or more of the peptide bonds are replaced by a retro-inverso pseudopeptide bond. Preferably the most N-terminal peptide bond is substituted, since such a substitution will confer resistance to proteolysis by exopeptidases acting on the N-terminus.

[0115] Peptoid derivatives of polypeptides represent another form of modified polypeptides that retain the important structural determinants for biological activity, yet eliminate the peptide bonds, thereby conferring resistance to proteolysis (Simon et al., Proc. Natl. Acad. Sci. USA 89: 9367-9371, 1992, and incorporated herein by reference).
Peptoids are oligomers of N-substituted glycines. A number of N-alkyl groups have been described, each corresponding to the side chaimof a natural amino acid.

F. POLYNUCLEOTIDES
[0116] The invention includes polynucleotides encoding peptides of the invention. Exemplary polynucleotides encode peptides including those listed in Table 1, and analogs, derivatives, amidated variations and conservative variations thereof, wherein the peptides have antimicrobial activity. The peptides of the invention include SEQ ID
NOS:1-2166, as well as the broader groups of peptides having hydrophilic and hydrophobic substitutions, and conservative variations thereof.
[0117] "Isolated" when used in reference to a polynucleotide, refers to a polynucleotide substantially free of proteins, lipids, nucleic acids, for example, with which it is naturally associated. As used herein, "polynucleotide" refers to a polymer of deoxyribonucleotides or ribonucleotides, in the form of a separate fragment or as a component of a larger construct. DNA encoding a peptide of the invention can be assembled from cDNA fragments or from oligonucleotides which provide a synthetic gene which is capable of being expressed in a recombinant transcriptional unit.
Polynucleotide sequences of the invention include DNA, RNA and cDNA sequences. A
polynucleotide sequence can be deduced from the genetic code, however, the degeneracy of the code must be taken into account. Polynucleotides of the invention include sequences which are degenerate as a result of the genetic code. Such polynucleotides are useful for the recombinant production of large quantities of a peptide of interest, such as the peptide of SEQ ID NOS: 1-2166.
[0118] "Recombinant" when used with reference, e.g., to a cell, or nucleic acid, protein, or vector, indicates that the cell, nucleic acid, protein or vector, has been modified by the introduction of a heterologous nucleic acid or protein or the alteration of a native nucleic acid or protein, or that the cell is derived from a cell so modified.
Thus, for example, recombinant cells express genes that are not found within the native (non-recombinant) form of the cell or express native genes that are otherwise abnormally expressed, under expressed or not expressed at all.
[0119] In the present invention, the polynucleotides encoding the peptides of the invention may be inserted into a recombinant "expression vector". The term "expression vector" refers to a plasmid, virus or other vehicle known in the art that has been manipulated by insertion or incorporation of genetic sequences. Such expression vectors of the invention are preferably plasmids that contain a promoter sequence that facilitates the efficient transcription of the inserted genetic sequence in the host. The expression vector typically contains an origin of replication, a promoter, as well as specific genes that allow phenotypic selection of the transformed cells. For example, the expression of the peptides of the invention can be placed under control of E. coli chromosomal DNA
comprising a lactose or lac operon which mediates lactose utilization by elaborating the enzyme beta-galactosidase. The lac control system can be induced by IPTG. A
plasmid can be constructed to contain the lac Iq repressor gene, permitting repression of the lac promoter until IPTG is added. Other promoter systems known in the art include beta lactamase, lambda promoters, the protein A promoter, and the tryptophan promoter systems. While these are the most commonly used, other microbial promoters, both inducible and constitutive, can be utilized as well. The vector contains a replicon site and control sequences which are derived from species compatible with the host cell. In addition, the vector may carry specific gene(s) which are capable of providing phenotypic selection in transformed cells. For example, the beta-lactamase gene confers ampicillin resistance to those transformed cells containing the vector with the beta-lactamase gene.
An exemplary expression system for production of the peptides of the invention is described in U.S. Pat. No. 5,707,855.
[0120] Transformation of a host cell with the polynucleotide may be carried out by conventional techniques known to those skilled in the art. For example, where the host is prokaryotic, such as E. coli, competent cells that are capable of DNA
uptake can be prepared from cells harvested after exponential growth and subsequently treated by the CaC12 method using procedures known in the art. Alternatively, MgC12 or RbCI
could be used.
[0121] In addition to conventional chemical methods of transformation, the plasmid vectors of the invention may be introduced into a host cell by physical means, such as by electroporation or microinjection. Electroporation allows transfer of the vector by high voltage electric impulse, which creates pores in the plasma membrane of the host and is performed according to methods known in the art. Additionally, cloned DNA can be introduced into host cells by protoplast fusion, using methods known in the art.
[0122] DNA sequences encoding the peptides can be expressed in vivo by DNA
transfer into a suitable host cell. "Host cells" of the invention are those in which a vector can be propagated and its DNA expressed. The term also includes any progeny of the subject host cell. It is understood that not all progeny are identical to the parental cell, since there may be mutations that occur during replication. However, such progeny are included when the terms above are used. Preferred host cells of the invention include E.
coli, S. aureus and P. aeruginosa, although other Gram-negative and Gram-positive organisms known in the art can be utilized as long as the expression vectors contain an origin of replication to permit expression in the host.
[0123] The polynucleotide sequence encoding the peptide used according to the method of the invention can be isolated from an organism or synthesized in the laboratory.
Specific DNA sequences encoding the peptide of interest can be obtained by: 1) isolation of a double-stranded DNA sequence from the genomic DNA; 2) chemical manufacture of a DNA sequence to provide the necessary codons for the peptide of interest;
and 3) in vitro synthesis of a double-stranded DNA sequence by reverse transcription of mRNA
isolated from a donor cell. In the latter case, a double-stranded DNA complement of mRNA is eventually formed that is generally referred to as cDNA.
[0124] The synthesis of DNA sequences is frequently the method of choice when the entire sequence of amino acid residues of the desired peptide product is known. In the present invention, the synthesis of a DNA sequence has the advantage of allowing the incorporation of codons that are more likely to be recognized by a bacterial host, thereby permitting high level expression without difficulties in translation. In addition, virtually any peptide can be synthesized, including those encoding natural peptides, variants of the same, or synthetic peptides.
[0125] When the entire sequence of the desired peptide is not known, the direct synthesis of DNA sequences is not possible and the method of choice is the formation of cDNA sequences. Among the standard procedures for isolating cDNA sequences of interest is the formation of plasmid or phage containing cDNA libraries that are derived from reverse transcription of mRNA that is abundant in donor cells that have a high level of genetic expression. When used in combination with polymerase chain reaction technology, even rare expression products can be cloned. In those cases where significant portions of the amino acid sequence of the peptide are known, the production of labeled single or double-stranded DNA or RNA probe sequences duplicating a sequence putatively present in the target cDNA may be employed in DNA/DNA hybridization procedures which are carried out on cloned copies of the cDNA which have been denatured into a single stranded form. Jay et al., Nuc. Acid Res. 11: 2325, 1983.

G. METHODS OF USE
[0126] The invention also provides a method of inhibiting the growth of bacteria including contacting the bacteria with an inhibiting effective amount of a peptide of the invention, including SEQ ID NOS: 1-2166, and analogs, derivatives, amidated variations and conservative variations thereof, wherein the peptides have antimicrobial activity.
[0127] The term "contacting" refers to exposing the bacteria to the peptide so that the peptide can effectively inhibit, kill, or lyse bacteria, bind endotoxin (LPS), or permeabilize Gram-negative bacterial outer membranes. Contacting may be in vitro, for example by adding the peptide to a bacterial culture to test for susceptibility of the bacteria to the peptide. Contacting may be in vivo, for example administering the peptide to a subject with a bacterial disorder, such as septic shock or infection.
Contacting may further involve coating an object (e.g., medical device) such as a catheter to inhibit bacteria with which it comes into contact, thus preventing it from becoming colonized with the bacteria.
"Inhibiting" or "inhibiting effective amount" refers to the amount of peptide that is required to cause a bacteriostatic or bactericidal effect. Examples of bacteria that may be inhibited include Escherichia coli, Pseudomonas aeruginosa, Enterobacter cloacae, Salmonella enteritidis subspecies Typhimurium, Staphylococcus aureus, Enterococcus facaelis, Listeria monocytogenes, Corynebacterium xerosis, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus mitis and Staplzylococcuus epidermidis.
[0128] The method of inhibiting the growth of bacteria may further include the addition of antibiotics for combination or synergistic therapy. The appropriate antibiotic administered will typically depend on the susceptibility of the bacteria such as whether the bacteria is Gram negative or Gram positive, and will be easily discernable by one of skill in the art. Examples of particular classes of antibiotics useful for synergistic therapy with the peptides of the invention include aminoglycosides (e.g., tobramycin), penicillins (e.g., piperacillin), cephalosporins (e.g., ceftazidime), fluoroquinolones (e.g., ciprofloxacin), carbapenems (e.g., imipenem), tetracyclines and macrolides (e.g., erythromycin and clarithromycin). The method of inhibiting the growth of bacteria may further include the addition of antibiotics for combination or synergistic therapy. The appropriate antibiotic administered will typically depend on the susceptibility of the bacteria such as whether the bacteria is Gram negative or Gram positive, and will be easily discernable by one of skill in the art. Further to the antibiotics listed above, typical antibiotics include aminoglycosides (amikacin, gentamicin, kanamycin, netilmicin, t-obramycin, streptomycin), macrolides ( azithromycin, clarithromycin, erythromycin, erythromycin estolate/ethylsuccinate/ gluceptate/lactobionate/stearate), beta-lactams such as penicillins (e.g., penicillin G, penicillin V, methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin, ampicillin, amoxicillin, ticarcillin, carbenicillin, mezlocillin, azlocillin and piperacillin), or cephalosporins (e.g., cephalothin, cefazolin, cefaclor, cefamandole, cefoxitin, cefuroxime, cefonicid, cefmetazole, cefotetan, cefprozil, loracarbef, cefetamet, cefoperazone, cefotaxime, ceftizoxime, ceftriaxone, ceftazidime, cefepime, cefixime, cefpodoxime, and cefsulodin) or carbapenems (e.g., imipenem, meropenem, panipenem), or monobactams (e.g., aztreonam). Other classes of antibiotics include quinolones (e.g., fleroxacin, nalidixic acid, norfloxacin, ciprofloxacin, ofloxacin, enoxacin, lomefloxacin and cinoxacin), tetracyclines (e.g., doxycycline, minocycline, tetracycline), and glycopeptides (e.g., vancomycin, teicoplanin), for example. Other antibiotics include chloramphenicol, clindamycin, trimethoprim, sulfamethoxazole, nitrofurantoin, rifampin, linezolid, synercid, polymyxin B, colisitin, colimycin, methotrexate, daptomycin, phosphonomycin and mupirocin.
[0129] The peptides and/or analogs or derivatives thereof may be administered to any host, including a human or non-human animal, in an amount effective to inhibit not only growth of a bacterium, but also a virus, parasite or fungus. These peptides are useful as antimicrobial agents, antiviral agents, and antifungal agents. The peptides and/or analogs or derivatives thereof may be administered to any host, including a human or non-human animal, in an amount effective to inhibit not only growth of a bacterium, but also a virus or fungus. These peptides are useful as antimicrobial agents, antiviral agents, and antifungal agents.
[0130] In addition to being active against a broad range of pathogens, bactenecin has been shown to be cytotoxic to rat embryonic neurons, fetal rat astrocytes and human glioblastoma cells. Radermacher et al., J. Neuro. Res. 36: 657, 1993. Thus, it is envisioned that the peptides of the present invention can be used to inhibit the growth of a eukaryotic cell by contacting the eukaryotic cell with an inhibiting effective amount of a peptide of the invention. Such a method would be useful, for example, for inhibiting a cell proliferation-associated disorder in a subject having or at risk of having such a disorder.
The method can involve, for example, administering to the subject a therapeutically effective amount of a peptide of the present invention to inhibit the over-growth of cells in a subject in need of such treatment. Such disorders would include, for example, neurological related disorders.
[0131] The invention further provides a method of protecting objects from bacterial colonization. The peptides of the invention remain active when conjugated to solid surfaces. Thus, the peptides may be used for protecting objects such as medical devices from colonization with pathogenic bacteria by chemically conjugating, or coating by any other means, at least one peptide of the invention to the surface of the medical device. Such medical devices include indwelling catheters, and the like.

H. TREATMENT REGIMES
[0132] The invention provides pharmaceutical compositions comprising one or a combination of antimicrobial peptides, for example, formulated together with a pharmaceutically acceptable carrier. Some compositions include a combination of multiple (e.g., two or more) peptides of the invention. Some compositions include a combination of a peptide and/or peptides of the invention together with other drugs or agents (i.e., antimicrobial drugs and/or antimicrobial agents).
[0133] As used herein " pharmaceutically acceptable carrier" and "pharmaceutically acceptable excipient" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. In one embodiment, the carrier is suitable for parenteral administration. Alternatively, the carrier can be suitable for intravenous, intraperitoneal or intramuscular administration. In another embodiment, the carrier is suitable for oral administration. Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is compatible with the active compound, use thereof in the pharmaceutical compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.
[0134] "Pharmaceutically acceptable salts and esters" means salts and esters that are pharmaceutically acceptable and have the desired pharmacological properties. Such salts include salts that can be formed where acidic protons present in the compounds are capable of reacting with inorganic or organic bases. Suitable inorganic salts include those formed with the alkali metals, e.g. sodium and potassium, magnesium, calcium, and aluminum. Suitable organic salts include those formed with organic bases such as the amine bases, e.g. ethanolamine, diethanolamine, triethanolamine, tromethamine, N
methylglucamine, and the like. Such salts also include acid addition salts formed with inorganic acids (e.g., hydrochloric and hydrobromic acids) and organic acids (e.g. acetic acid, citric acid, maleic acid, and the alkane- and arene-sulfonic acids such as methanesulfonic acid and benzenesulfonic acid). Pharmaceutically acceptable esters include esters formed from carboxy, sulfonyloxy, and phosphonoxy groups present in the compounds, e.g. C1-6 alkyl esters. When there are two acidic groups present, a pharmaceutically acceptable salt or ester can be a mono-acid-mono-salt or ester or a di-salt or ester; and similarly where there are more than two acidic groups present, some or all of such groups can be salified or esterified. Compounds named in this invention can be present in unsalified or unesterified form, or in salified and/or esterified form, and the naming of such compounds is intended to include both the original (unsalified and unesterified) compound and its pharmaceutically acceptable salts and esters.
Also, certain compounds named in this invention may be present in more than one stereoisomeric form, and the naming of such compounds is intended to include all single stereoisomers and all mixtures (whether racemic or otherwise) of such stereoisomers.

[0135] "Pharmaceutically acceptable", "physiologically tolerable" and grammatical variations thereof, as they refer to compositions, carriers, diluents and reagents, are used interchangeably and represent that the materials are capable of administration to or upon a human without the production of undesirable physiological effects to a degree that would prohibit administration of the composition.
[0136] In prophylactic applications, pharmaceutical compositions or medicaments are administered to a patient susceptible to, or otherwise at risk of a disease or condition (i.e., as a result of bacteria, fungi, viruses, parasites or the like) in an amount sufficient to eliminate or reduce the risk, lessen the severity, or delay the outset of the disease, includ'uig biochemical, histologic and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease. In therapeutic applications, compositions or medicants are administered to a patient suspected of, or already suffering from such a disease or condition in an amount sufficient to cure, or at least partially arrest, the symptoms of the disease or condition (e.g., biochemical and/or histologic), including its complications and intermediate pathological phenotypes in development of the disease or condition. An amount adequate to accomplish therapeutic or prophylactic treatment is defined as a therapeutically- or prophylactically-effective dose. In both prophylactic and therapeutic regimes, agents are usually administered in several dosages until a sufficient response has been achieved.
Typically, the response is monitored and repeated dosages are given if the response starts to wane.
[0137] The pharmaceutical composition of the present invention should be sterile and fluid to the extent that the composition is deliverable by syringe. In addition to water, the carrier can be an isotonic buffered saline solution, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by use of coating such as lecithin, by maintenance of required particle size in the case of dispersion and by use of surfactants. In many cases, it is preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol or sorbitol, and sodium chloride in the composition. Long-term absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.
[0138] When the active compound is suitably protected, as described above, the compound can be orally administered, for example, with an inert diluent or an assimilable edible carrier.
[0139] Pharmaceutical compositions of the invention also can be administered in combination therapy, i.e., combined with other agents. For example, in treatment of bacteria, the combination therapy can include a composition of the present invention with at least one agent or other conventional therapy. "Concomitant administration"
of a known antimicrobial drug with a pharmaceutical composition of the present invention means administration of the drug and the peptide and/or protein composition at such time that both the known drug and the composition of the present invention will have a therapeutic effect. Such concomitant administration can involve concurrent (i.e., at the same time), prior, or subsequent administration of the antimicrobial drug with respect to the administration of a compound of the present invention. A person of ordinary skill in the art, would have no difficulty determining the appropriate timing, sequence and dosages of administration for particular drugs and compositions of the present invention 1. ROUTES OF ADMINISTRATION
[0140] A composition of the present invention can be administered by a variety of methods known in the art. The route and/or mode of administration vary depending upon the desired results. The phrases "parenteral administration" and "administered parenterally" mean modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion.
The peptide of the invention can be administered parenterally by injection or by gradual infusion over time. The peptide can also be prepared with carriers that protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems Further methods for delivery of the peptide include orally, by encapsulation in microspheres or proteinoids, by aerosol delivery to the lungs, or transdermally by iontophoresis or transdermal electroporation. To administer a peptide of the invention by certain routes of administration, it can be necessary to coat the compound with, or co-administer the compound with, a material to prevent its inactivation. The method of the invention also includes delivery systems such as microencapsulation of peptides into liposomes or a diluent.
Microencapsulation also allows co-entrapment of antimicrobial molecules along with the antigens, so that these molecules, such as antibiotics, may be delivered to a site in need of such treatment in conjunction with the peptides of the invention. Liposomes in the blood stream are generally taken up by the liver and spleen. Pharmaceutically acceptable diluents include saline and aqueous buffer solutions. Liposomes include water-in-oil-in-water CGF
emulsions as well as conventional liposomes. Strejan et al., J. Neuroimmunol.
7: 27, 1984.
Thus, the method of the invention is particularly useful for delivering antimicrobial peptides to such organs. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are described by e.g., Robinson, 1978, Sustained and Controlled Release Drug Delivery Systems.
Other methods of administration will be known to those skilled in the art.
[0141] Preparations for parenteral administration of a peptide of the invention include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like.
[0142] Therapeutic compositions typically must be sterile, substantially isotonic, and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it is preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.
[0143] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by sterilization microfiltration.
Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
Therapeutic compositions can also be administered with medical devices known in the art.
For example, in a preferred embodiment, a therapeutic composition of the invention can be administered with a needleless hypodermic injection device, such as the devices disclosed in, e.g., U.S. Patent Nos. 5,399,163, 5,383,851, 5,312,335, 5,064,413, 4,941,880, 4,790,824, or 4,596,556. Examples of implants and modules useful in the present invention include: U.S. Patent No. 4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; U.S. Patent No.
4,486,194, which discloses a therapeutic device for administering medicants through the skin; U.S.
Patent No. 4,447,233, which discloses a medication infusion pump for delivering medication at a precise infusion rate; U.S. Patent No. 4,447,224, which discloses a variable flow implantable infusion apparatus for continuous drug delivery;
U.S. Patent No.
4,439,196, which discloses an osmotic drug delivery system having multi-chamber compartments; and U.S. Patent No. 4,475,196, which discloses an osmotic drug delivery system. Many other such implants, delivery systems, and modules are known.
[0144] When the peptides of the present invention are administered as pharmaceuticals, to humans and animals, they can be given alone or as a pharmaceutical composition containing, for example, 0.01 to 99.5% (or 0.1 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

J. EFFECTIVE DOSAGES
[0145] "Therapeutically effective amount" as used herein for treatment of antimicrobial related diseases and conditions refers to the amount of peptide used that is of sufficient quantity to decrease the numbers of bacteria, viruses, fungi, and parasites in the body of a subject. The dosage ranges for the administration of peptides are those large enough to produce the desired effect. The amount of peptide adequate to accomplish this is defined as a "therapeutically effective dose." The dosage schedule and amounts effective for this use, i.e., the "dosing regimen," will depend upon a variety of factors, including the stage of the disease or condition, the severity of the disease or condition, the general state of the patient's health, the patient's physical status, age, pharmaceutical formulation and concentration of active agent, and the like. In calculating the dosage regimen for a patient, the mode of administration also is taken into consideration. The dosage regimen must also take into consideration the pharmacokinetics, i.e., the pharmaceutical composition's rate of absorption, bioavailability, metabolism, clearance, and the like. See, e.g., the latest Remington's (Remington's Pharmaceutical Science, Mack Publishing Company, Easton, PA); Egleton, Peptides 18: 1431-1439, 1997; Langer, Science 249: 1527-1533, 1990. The dosage regimen can be adjusted by the individual physician in the event of any contraindications.
[0146] Dosage regimens of the pharmaceutical compositions of the present invention are adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus can be administered, several divided doses can be administered over time or the dose can be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.
[0147] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention can be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level depends upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors.
[0148] A physician or veterinarian can start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In general, a suitable daily dose of a compound of the invention is that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose generally depends upon the factors described above. It is preferred that administration be intravenous, intramuscular, intraperitoneal, or subcutaneous, or administered proximal to the site of the target. If desired, the effective daily dose of a therapeutic composition can be administered as two, three, four, five, six or more sub-doses administered separately at appropri-ate intervals throughout the day, optionally, in unit dosage forms. While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).

[0149] An effective dose of each of the peptides disclosed herein as potential therapeutics for use in treating microbial diseases and conditions is from about 1.gg to 500 mg/kg body weight, per single administration, which can readily be determined by one skilled in the art. As discussed above, the dosage depends upon the age, sex, health, and weight of the recipient, kind of concurrent therapy, if any, and frequency of treatment.
Other effective dosage range upper limits are 100 mg/kg body weight, 50 mg/kg body weight, 25 mg/kg body weight, and 10 mg/kg body weight.

[0150] The dosage and frequency of administration can vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, a relatively low dosage is administered at relatively infrequent intervals over a long period of time. Some patients continue to receive treatment for the rest of their lives. In therapeutic applications, a relatively high dosage at relatively short intervals is sometimes required until progression of the disease is reduced or tenninated, and preferably until the patient shows partial or complete amelioration of symptoms of disease.
Thereafter, the patent can be administered a prophylactic regime.

[0151] Some compounds of the invention can be formulated to ensure proper distribution in vivo. For example, the blood-brain barrier (BBB) excludes many highly hydrophilic compounds. To ensure that the therapeutic compounds of the invention cross the BBB (if desired), they can be formulated, for example, in liposomes. For methods of manufacturing liposomes, See, e.g., U.S. Patents 4,522,811; 5,374,548; and 5,399,331.
The liposomes can comprise one or more moieties which are selectively transported into specific cells or organs, thus enhance targeted drug delivery (See, e.g., Ranade, J. Clin.
Pharmacol. 29: 685, 1989). Exemplary targeting moieties include folate or biotin (See, e.g., U.S. Patent 5,416,016 to Low et al.,); mannosides (Umezawa et al., Biochem.
Biophys. Res. Conamun. 153: 1038, 1988); antibodies (Bloeman et al., FEBS
Lett. 357:
140, 1995; Owais et al., Antimicrob. Agents Chemothey: 39: 180, 1995);
surfactant protein A receptor (Briscoe et al., Am. J. Physiol. 1233: 134, 1995), different species of which can comprise the formulations of the inventions, as well as components of the invented molecules; p120 (Schreier et al., J. Biol. Chem. 269: 9090, 1994);
See also Keinanen et al., FEBS Lett. 346: 123, 1994; Killion et al., Immunonaethods 4:
273, 1994.
In some methods, the therapeutic compounds of the invention are formulated in liposomes;

in a more preferred embodiment, the liposomes include a targeting moiety. In some methods, the therapeutic compounds in the liposomes are delivered by bolus injection to a site proximal to the tumor or infection. The composition should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
[0152] "Bactericidal amount" as used herein refers to an amount sufficient to achieve a bacteria-killing blood concentration in the subject receiving the treatment. The bactericidal amount of antibiotic generally recognized as safe for administration to a human is well known in the art, and as is known in the art, varies with the specific antibiotic and the type of bacterial infection being treated.
[0153] Because of the antibiotic, antimicrobial, and antiviral properties of the peptides, they may also be used as preservatives or sterillants of materials susceptible to microbial or viral contamination. The peptides of the invention can be utilized as broad spectrum antimicrobial agents directed toward various specific applications.
Such applications include use of the peptides as preservatives in processed foods (organisms including Salmonella, Yersinia, Shigella), either alone or in combination with antibacterial food additives such as lysozymes; as a topical agent (Pseudomonas, Streptococcus) and to kill odor producing microbes (Micrococci). The relative effectiveness of the peptides of the invention for the applications described can be readily determined by one of skill in the art by determining the sensitivity of any organism to one of the peptides.

K. FORMULATION
[0154] Typically, compositions are prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection can also be prepared. The preparation also can be emulsified or encapsulated in liposomes or micro particles such as polylactide, polyglycolide, or copolymer for enhanced adjuvant effect, as discussed above. Langer, Science 249: 1527, 1990 and Hanes, Advanced Drug Delivery Reviews 28: 97-119, 1997. The agents of this invention can be administered in the form of a depot injection or implant preparation which can be formulated in such a manner as to permit a sustained or pulsatile release of the active ingredient.

[0155] Additional formulations suitable for other modes of administration include oral, intranasal, and pulmonary formulations, suppositories, and transdermal applications.
[0156] For suppositories, binders and carriers include, for example, polyalkylene glycols or triglycerides; such suppositories can be formed from mixtures containing the active ingredient in the range of 0.5% to 10%, preferably 1%-2%. Oral formulations include excipients, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, and magnesium carbonate. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders and contain 10%-95% of active ingredient, preferably 25%-70%.
[0157] Topical application can result in transdermal or intradermal delivery.
Topical administration can be facilitated by co-administration of the agent with cholera toxin or detoxified derivatives or subunits thereof or other similar bacterial toxins. Glenn et al., Nature 391: 851, 1998. Co-administration can be achieved by using the components as a mixture or as linked molecules obtained by chemical crosslinking or expression as a fusion protein.
[0158] Alternatively, transdermal delivery can be achieved using a skin patch or using transferosomes. Paul et al., Eur. J. Immunol. 25: 3521-24, 1995; Cevc et al., Biochem. Biophys. Acta 1368: 201-15, 1998.
[0159] The pharmaceutical compositions are generally formulated as sterile, substantially isotonic and in full compliance with all Good Manufacturing Practice (GMP) regulations of the U.S. Food and Drug Administration.
[0160] From the foregoing description, various modifications and changes in the compositions and methods will occur to those skilled in the art. All such modifications coming within the scope of the appended claims are intended to be included therein. Each recited range includes all combinations and sub-combinations of ranges, as well as specific numerals contained therein.
[0161] All publications and patent documents cited above are hereby incorporated by reference in their entirety for all purposes to the same extent as if each were so individually denoted.
[0162] Although the foregoing invention has been described in detail by way of example for purposes of clarity of understanding, it will be apparent to the artisan that certain changes and modifications are comprehended by the disclosure and can be practiced without undue experimentation within the scope of the appended claims, which are presented by way of illustration not limitation.

EXEMPLARY EMBODIMENTS
EXANH'LE 1 MATERIALS AND METHODS AND PEPTIDES
[0163] Peptide Synthesis - Peptide syntheses on cellulose were performed using a pipetting robot (Abimed, Langenfeld, Germany) and Whatman 50 cellulose membranes (Whatman, Maidstone, United Kingdom) as described previously. Kramer et al., Comp.
Meth. Enzymol. 6: 388-395, 1994; Kramer et al., Cell 91: 799-809, 1997. The HPLC
purified peptides used for further characterization (CD, membrane permeability, MIC) were purchased from Thermo Electron Corperation (Ulm, Germany).

Bac001 = Bac2A RLARIVVIRVAR SEQ ID NO: 1 Bac002 RRIARVIVAVLR SEQ ID NO: 2 Bac003 ARRLIVRVRVIA SEQ ID NO: 3 Bac004 IRARIAVRRVVL SEQ ID NO: 4 Bac005 IVRVAVALRRIR SEQ ID NO: 5 Bac006 VRIRARRVILVA SEQ ID NO: 6 Bac007 RRLVAIVAVRRI SEQ ID NO: 7 Bac008 VLIRIRRVARAV SEQ ID NO: 8 Bac009 IIRAALRRVRVV SEQ ID NO: 9 BacOlO AAVRRRVRLVII SEQ ID NO: 10 BacOll AVRVRRRAILVI SEQ ID NO: 11 Bac012 IAARRLIRVVRV SEQ ID NO: 12 Bac013 VARIVVRLIRAR SEQ ID NO: 13 Bac014 RAVAVIIRLRRV SEQ ID NO: 14 Bac015 AVRAIRVLRVIR SEQ ID NO: 15 Bac016 RARIVRVRVILA SEQ ID NO: 16 Bac017 VILARRRVRIAV SEQ ID NO: 17 Bac018 RRVAIVVIAR.LR SEQ ID NO: 18 Bac019 ILVARVIRRRVA SEQ ID NO: 19 Bac020 RRAAVVLIVIRR SEQ ID NO: 20 Bac021 ARIARRVRILVV SEQ ID NO: 21 Bac022 ILRRVRVRAVAI SEQ ID NO: 22 Bac023 RRRAIVRVVAIL SEQ ID NO: 23 Bac024 RAIIRRVLVRVA SEQ ID NO: 24 Bac025 ARAILIRVVRRV SEQ ID NO: 25 Bac026 IARRIVAVRLRV SEQ ID NO: 26 Bac027 RVLIARVVRAIR SEQ ID NO: 27 Bac028 VIVRLAARRVRI SEQ ID NO: 28 Bac029 IILAVRAVRRVR SEQ ID NO: 29 Bac030 IVVRRRRAALVI SEQ ID NO: 30 Bac031 LAIVRRARVRIV SEQ ID NO: 31 Bac032 ARRARIRILVVV SEQ ID NO: 32 Bac033 IRVRRLVAAVIR SEQ ID NO: 33 Bac034 VRLRIRVAVIRA SEQ ID NO: 34 Bac035 RVLRVVRAAIRI SEQ ID NO: 35 Bac036 RARRVRVLIAIV SEQ ID NO: 36 Bac037 RAIRVRRIVLAV SEQ ID NO: 37 Bac038 VVIRAAIRRVRL SEQ ID NO: 38 Bac039 RIVLRRAAVIRV SEQ ID NO: 39 Bac040 VLARVVARRIRI SEQ ID NO: 40 Bac041 RLRVAIVAIVRR SEQ ID NO: 41 Bac042 ILVIVRRRARAV SEQ ID NO: 42 Bac043 RVLIVIRARRVA SEQ ID NO: 43 Bac044 VIRRRRILAAVV SEQ ID NO: 44 Bac045 VIALRIAVRRVR SEQ ID NO: 45 Bac046 RRRVIVAVLARI SEQ ID NO: 46 Bac047 RVLIAARVIRRV SEQ ID NO: 47 Bac048 VVRALRRIIARV SEQ ID NO: 48 Bac049 VIALVRARVRRI SEQ ID NO: 49 Bac050 RRVIAIAVRRLV SEQ ID NO: 50 BaclOl RLARIVVIRVA SEQ ID NO: 51 Bacl02 LARIVVIRVAR SEQ ID NO: 52 Bacl03 RLARIVVIRV SEQ ID NO: 53 Bac104 LARIVVIRVA SEQ ID NO: 54 Bac105 ARIVVIRVAR SEQ ID NO: 55 Bac106 RLARIVVIR SEQ ID NO: 56 Bac107 LARIVVIRV SEQ ID NO: 57 Bac108 ARIVVIRVA SEQ ID NO: 58 Bac109 RIVVIRVAR SEQ ID NO: 59 Bac110 RLARIVVI SEQ ID NO: 60 Baclll LARIVVIR SEQ ID NO: 61 Bacl12 ARIVVIRV SEQ ID NO: 62 Bacl13 RIVVIRVA SEQ ID NO: 63 Bacl14 IVVIRVAR SEQ ID NO: 64 Bacl15 RLARIVV SEQ ID NO: 65 Bacl16 LARIVVI SEQ ID NO: 66 Bacl17 ARIVVIR SEQ ID NO: 67 Bacl18 RIVVIRV SEQ ID NO: 68 Bac119 IVVIRVA SEQ ID NO: 69 Bac120 VVIRVAR SEQ ID NO: 70 Bacl2l RLARIV SEQ ID NO: 71 Bac122 LARIVV SEQ ID NO: 72 Bac123 ARIVVI SEQ ID NO: 73 Bac124 RIVVIR SEQ ID NO: 74 Bac125 IVVIRV SEQ ID NO: 75 Bac126 VVIRVA SEQ ID NO: 76 Bac127 VIRVAR SEQ ID NO: 77 Bac128 RLARIV SEQ ID NO: 78 Bac129 LARIVV SEQ ID NO: 79 Bac130 ARIVVI SEQ ID NO: 80 Bacl3l RIVVIR SEQ ID NO: 81 Bac132 IVVIRV SEQ ID NO: 82 Bac133 VVIRVA SEQ ID NO: 83 Bac134 VIRVAR SEQ ID NO: 84 Bacl35 RLARI SEQ ID NO: 85 Bac136 LARIV SEQ ID NO: 86 Bac137 ARIVV SEQ ID NO: 87 Bac138 RIVVI SEQ ID NO: 88 Bac139 IVVIR SEQ ID NO: 89 Bac140 VVIRV SEQ ID NO: 90 Bacl4l VIRVA SEQ ID NO: 91 Bac142 IRVAR SEQ ID NO: 92 Bac201 ALARIVVIRVAR SEQ ID NO: 93 Bac202 CLARIVVIRVAR SEQ ID NO: 94 Bac203 DLARIVVIRVAR SEQ ID NO: 95 Bac204 ELARIVVIRVAR SEQ ID NO: 96 Bac205 FLARIVVIRVAR SEQ ID NO: 97 Bac206 GLARIVVIRVAR SEQ ID NO: 98 Bac207 HLARIVVIRVAR SEQ ID NO: 99 Bac208 ILARIVVIRVAR SEQ ID NO: 100 Bac209 KLARIVVIRVAR SEQ ID NO: 101 Bac210 LLARIVVIRVAR SEQ ID NO: 102 Bac2ll MLARIVVIRVAR SEQ ID NO: 103 Bac212 NLARIVVIRVAR SEQ ID NO: 104 Bac213 PLARIVVIRVAR SEQ ID NO: 105 Bac214 QLARIVVIRVAR SEQ ID NO: 106 Bac215 SLARIVVIRVAR SEQ ID NO: 107 Bac216 TLARIVVIRVAR SEQ ID NO: 108 Bac217 VLARIVVIRVAR SEQ ID NO: 109 Bac218 WLARIVVIRVAR SEQ ID NO: 110 Bac219 YLARIVVIRVAR SEQ ID NO: 111 Bac220 RAARIVVIRVAR SEQ ID NO: 112 Bac221 RCARIVVIRVAR SEQ ID NO: 113 Bac222 RDARIVVIRVAR SEQ ID NO: 114 Bac223 REARIVVIRVAR SEQ ID NO: 115 Bac224 RFARIVVIRVAR SEQ ID NO: 116 Bac225 RGARIVVIRVAR SEQ ID NO: 117 Bac226 RHARIVVIRVAR SEQ ID NO: 118 Bac227 RIARIVVIRVAR SEQ ID NO: 119 Bac228 RKARIVVIRVAR SEQ ID NO: 120 Bac229 RMARIVVIRVAR SEQ ID NO: 121 Bac230 RNARIVVIRVAR SEQ ID NO: 122 Bac231 RPARIVVIRVAR SEQ ID NO: 123 Bac232 RQARIVVIRVAR SEQ ID NO: 124 Bac233 RRARIVVIRVAR SEQ ID NO: 125 Bac234 RSARIVVIRVAR SEQ ID NO: 126 Bac235 RTARIVVIRVAR SEQ ID NO: 127 Bac236 RVARIVVIRVAR SEQ ID NO: 128 Bac237 RWARIVVIRVAR SEQ ID NO: 129 Bac238 RYARIVVIRVAR SEQ ID NO: 130 Bac239 RLCRIVVIRVAR SEQ ID NO: 131 Bac240 RLDRIVVIRVAR SEQ ID NO: 132 Bac241 RLERIVVIRVAR SEQ ID NO: 133 Bac242 RLFRIVVIRVAR SEQ ID NO: 134 Bac243 RLGRIVVIRVAR SEQ ID NO: 135 Bac244 RLHRIVVIRVAR SEQ ID NO: 136 Bac245 RLIRIVVIRVAR SEQ ID NO: 137 Bac246 RLKRIVVIRVAR SEQ ID NO: 138 Bac247 RLLRIVVIRVAR SEQ ID NO: 139 Bac248 RLMRIVVIRVAR SEQ ID NO: 140 Bac249 RLNRIVVIRVAR SEQ ID NO: 141 Bac250 RLPRIVVIRVAR SEQ ID NO: 142 Bac251 RLQRIVVIRVAR SEQ ID NO: 143 Bac252 RLRRIVVIRVAR SEQ ID NO: 144 Bac253 RLSRIVVIRVAR SEQ ID NO: 145 Bac254 RLTRIVVIRVAR SEQ ID NO: 146 Bac255 RLVRIVVIRVAR SEQ ID NO: 147 Bac256 RLWRIVVIRVAR SEQ ID NO: 148 Bac257 RLYRIVVIRVAR SEQ ID NO: 149 Bac258 RLAAIVVIRVAR SEQ ID NO: 150 Bac259 RLACIVVIRVAR SEQ ID NO: 151 Bac260 RLADIVVIRVAR SEQ ID NO: 152 Bac261 RLAEIVVIRVAR SEQ ID NO: 153 Bac262 RLAFIVVIRVAR SEQ ID NO: 154 Bac263 RLAGIVVIRVAR SEQ ID NO: 155 Bac264 RLAHIVVIRVAR SEQ ID NO: 156 Bac265 RLAIIVVIRVAR SEQ ID NO: 157 Bac266 RLAKIVVIRVAR SEQ ID NO: 158 Bac267 RLALIVVIRVAR SEQ ID NO: 159 Bac268 RLAMIVVIRVAR SEQ ID NO: 160 Bac269 RLANIVVIRVAR SEQ ID NO: 161 Bac270 RLAPIVVIRVAR SEQ ID NO: 162 Bac271 RLAQIVVIRVAR SEQ ID NO: 163 Bac272 RLASIVVIRVAR SEQ ID NO: 164 Bac273 RLATIVVIRVAR SEQ ID NO: 165 Bac274 RLAVIVVIRVAR SEQ ID NO: 166 Bac275 RLAWIVVIRVAR SEQ ID NO: 167 Bac276 RLAYIVVIRVAR SEQ ID NO: 168 Bac277 RLARAVVIRVAR SEQ ID NO: 169 Bac278 RLARCVVIRVAR SEQ ID NO: 170 Bac279 RLARDVVIRVAR SEQ ID NO: 171 Bac280 RLAREVVIRVAR SEQ ID NO: 172 Bac281 RLARFVVIRVAR SEQ ID NO: 173 Bac282 RLARGVVIRVAR SEQ ID NO: 174 Bac283 RLARHVVIRVAR SEQ ID NO: 175 Bac284 RLARKVVIRVAR SEQ ID NO: 176 Bac285 RLARLVVIRVAR SEQ ID NO: 177 Bac286 RLARMVVIRVAR SEQ ID NO: 178 Bac287 RLARNVVIRVAR SEQ ID NO: 179 Bac288 RLARPVVIRVAR SEQ ID NO: 180 Bac289 RLARQVVIRVAR SEQ ID NO: 181 Bac290 RLARRVVIRVAR SEQ ID NO: 182 Bac291 RLARSVVIRVAR SEQ ID NO: 183 Bac292 RLARTVVIRVAR SEQ ID NO: 184 Bac293 RLARVVVIRVAR SEQ ID NO: 185 Bac294 RLARWVVIRVAR SEQ ID NO: 186 Bac295 RLARYVVIRVAR SEQ ID NO: 187 Bac296 RLARIAVIRVAR SEQ ID NO: 188 Bac297 RLARICVIRVAR SEQ ID NO: 189 Bac298 RLARIDVIRVAR SEQ ID NO: 190 Bac299 RLARIEVIRVAR SEQ ID NO: 191 Bac300 RLARIFVIRVAR SEQ ID NO: 192 Bac301 RLARIGVIRVAR SEQ ID NO: 193 Bac302 RLARIHVIRVAR SEQ ID NO: 194 Bac303 RLARIIVIRVAR SEQ ID NO: 195 Bac304 RLARIKVIRVAR SEQ ID NO: 196 Bac305 RLARILVIRVAR SEQ ID NO: 197 Bac306 RLARIMVIRVAR SEQ ID NO: 198 Bac307 RLARINVIRVAR SEQ ID NO: 199 Bac308 RLARIPVIRVAR SEQ ID NO: 200 Bac309 RLARIQVIRVAR SEQ ID NO: 201 Bac310 RLARIRVIRVAR SEQ ID NO: 202 Bac3ll RLARISVIRVAR SEQ ID NO: 203 Bac312 RLARITVIRVAR SEQ ID NO: 204 Bac313 RLARIWVIRVAR SEQ ID NO: 205 Bac314 RLARIYVIRVAR SEQ ID NO: 206 Bac315 RLARIVAIRVAR SEQ ID NO: 207 Bac316 RLARIVCIRVAR SEQ ID NO: 208 Bac317 RLARIVDIRVAR SEQ ID NO: 209 Bac318 RLARIVEIRVAR SEQ ID NO: 210 Bac319 RLARIVFIRVAR SEQ ID NO: 211 Bac320 RLARIVGIRVAR SEQ ID NO: 212 Bac321 RLARIVHIRVAR SEQ ID NO: 213 Bac322 RLARIVIIRVAR SEQ ID NO: 214 Bac323 RLARIVKIRVAR SEQ ID NO: 215 Bac324 RLARIVLIRVAR SEQ ID NO: 216 Bac325 RLARIVMIRVAR SEQ ID NO: 217 Bac326 RLARIVNIRVAR SEQ ID NO: 218 Bac327 RLARIVPIRVAR SEQ ID NO: 219 Bac328 RLARIVQIRVAR SEQ ID NO: 220 Bac329 RLARIVRIRVAR SEQ ID NO: 221 Bac330 RLARIVSIRVAR SEQ ID NO: 222 Bac331 RLARIVTIRVAR SEQ ID NO: 223 Bac332 RLARIVWIRVAR SEQ ID NO: 224 Bac333 RLARIVYIRVAR SEQ ID NO: 225 Bac334 RLARIVVARVAR SEQ ID NO: 226 Bac335 RLARIVVCRVAR SEQ ID NO: 227 Bac336 RLARIVVDRVAR SEQ ID NO: 228 Bac337 RLARIVVERVAR SEQ ID NO: 229 Bac338 RLARIVVFRVAR SEQ ID NO: 230 Bac339 RLARIVVGRVAR SEQ ID NO: 231 Bac340 RLARIVVHRVAR SEQ ID NO: 232 Bac341 RLARIVVKRVAR SEQ ID NO: 233 Bac342 RLARIVVLRVAR SEQ ID NO: 234 Bac343 RLARIVVMRVAR SEQ ID NO: 235 Bac344 RLARIVVNRVAR SEQ ID NO: 236 Bac345 RLARIVVPRVAR SEQ ID NO: 237 Bac346 RLARIVVQRVAR SEQ ID NO: 238 Bac347 RLARIVVRRVAR SEQ ID NO: 239 Bac348 RLARIVVSRVAR SEQ ID NO: 240 Bac349 RLARIVVTRVAR SEQ ID NO: 241 Bac350 RLARIVVVRVAR SEQ ID NO: 242 Bac351 RLARIVVWRVAR SEQ ID NO: 243 Bac352 RLARIVVYRVAR SEQ ID NO: 244 Bac353 RLARIVVIAVAR SEQ ID NO: 245 Bac354 RLARIVVICVAR SEQ ID NO: 246 Bac355 RLARIVVIDVAR SEQ ID NO: 247 Bac356 RLARIVVIEVAR SEQ ID NO: 248 Bac357 RLARIVVIFVAR SEQ ID NO: 249 Bac358 RLARIVVIGVAR SEQ ID NO: 250 Bac359 RLARIVVIHVAR SEQ ID NO: 251 Bac360 RLARIVVIIVAR SEQ ID NO: 252 Bac361 RLARIVVIKVAR SEQ ID NO: 253 Bac362 RLARIVVILVAR SEQ ID NO: 254 Bac363 RLARIVVIMVAR SEQ ID NO: 255 Bac364 RLARIVVINVAR SEQ ID NO: 256 Bac365 RLARIVVIPVAR SEQ ID NO: 257 Bac366 RLARIVVIQVAR SEQ ID NO: 258 Bac367 RLARIVVISVAR SEQ ID NO: 259 Bac368 RLARIVVITVAR SEQ ID NO: 260 Bac369 RLARIVVIVVAR SEQ ID NO: 261 Bac370 RLARIVVIWVAR SEQ ID NO: 262 Bac371 RLARIVVIYVAR SEQ ID NO: 263 Bac372 RLARIVVIRAAR SEQ ID NO: 264 Bac373 RLARIVVIRCAR SEQ ID NO: 265 Bac374 RLARIVVIRDAR SEQ ID NO: 266 Bac375 RLARIVVIREAR SEQ ID NO: 267 Bac376 RLARIVVIRFAR SEQ ID NO: 268 Bac377 RLARIVVIRGAR SEQ ID NO: 269 Bac378 RLARIVVIRHAR SEQ ID NO: 270 Bac379 RLARIVVIRIAR SEQ ID NO: 271 Bac380 RLARIVVIRKAR SEQ ID NO: 272 Bac381 RLARIVVIRLAR SEQ ID NO: 273 Bac382 RLARIVVIRMAR SEQ ID NO: 274 Bac383 RLARIVVIRNAR SEQ ID NO: 275 Bac384 RLARIVVIRPAR SEQ ID NO: 276 Bac385 RLARIVVIRQAR SEQ ID NO: 277 Bac386 RLARIVVIRRAR SEQ ID NO: 278 Bac387 RLARIVVIRSAR SEQ ID NO: 279 Bac388 RLARIVVIRTAR SEQ ID NO: 280 Bac389 RLARIVVIRWAR SEQ ID NO: 281 Bac390 RLARIVVIRYAR SEQ ID NO: 282 Bac391 RLARIVVIRVCR SEQ ID NO: 283 Bac392 RLARIVVIRVDR SEQ ID NO: 284 Bac393 RLARIVVIRVER SEQ ID NO: 285 Bac394 RLARIVVIRVFR SEQ ID NO: 286 Bac395 RLARIVVIRVGR SEQ ID NO: 287 Bac396 RLARIVVIRVHR SEQ ID NO: 288 Bac397 RLARIVVIRVIR SEQ ID NO: 289 Bac398 RLARIVVIRVKR SEQ ID NO: 290 Bac399 RLARIVVIRVLR SEQ ID NO: 291 - Bac400 RLARIVVIRVMR SEQ ID NO: 292 Bac401 RLARIVVIRVNR SEQ ID NO: 293 Bac402 RLARIVVIRVPR SEQ ID NO: 294 Bac403 RLARIVVIRVQR SEQ ID NO: 295 Bac404 RLARIVVIRVRR SEQ ID NO: 296 Bac405 RLARIVVIRVSR SEQ ID NO: 297 Bac406 RLARIVVIRVTR SEQ ID NO: 298 Bac407 RLARIVVIRVVR SEQ ID NO: 299 Bac408 RLARIVVIRVWR SEQ ID NO: 300 Bac409 RLARIVVIRVYR SEQ ID NO: 301 Bac410 RLARIVVIRVAA SEQ ID NO: 302 Bac4ll RLARIVVIRVAC SEQ ID NO: 303 Bac412 RLARIVVIRVAD SEQ ID NO: 304 Bac413 RLARIVVIRVAE SEQ ID NO: 305 Bac414 RLARIVVIRVAF SEQ ID NO: 306 Bac415 RLARIVVIRVAG SEQ ID NO: 307 Bac416 RLARIVVIRVAH SEQ ID NO: 308 Bac417 RLARIVVIRVAI SEQ ID NO: 309 Bac418 RLARIVVIRVAK SEQ ID NO: 310 Bac419 RLARIVVIRVAL SEQ ID NO: 311 Bac420 RLARIVVIRVAM SEQ ID NO: 312 Bac421 RLARIVVIRVAN SEQ ID NO: 313 Bac422 RLARIVVIRVAP SEQ ID NO: 314 Bac423 RLARIVVIRVAQ SEQ ID NO: 315 Bac424 RLARIVVIRVAS SEQ ID NO: 316 Bac425 RLARIVVIRVAT SEQ ID NO: 317 Bac426 RLARIVVIRVAV SEQ ID NO: 318 Bac427 RLARIVVIRVAW SEQ ID NO: 319 Bac428 RLARIVVIRVAY SEQ ID NO: 320 Bac429 GATPEDLNQKLS SEQ ID NO: 321 Bac430 RRWRIVVIRVRR SEQ ID NO: 322 Bac431 RRWKIVVIRWRR SEQ ID NO: 323 Bac432 RWWKIWVIRWWR SEQ ID NO: 324 Bac433 RLRRIVVIRVRR SEQ ID NO: 325 Bac434 KIWVIRWR SEQ ID NO: 326 Bac435 RIWVIRWR SEQ ID NO: 327 Bac436 RIWVIWRR SEQ ID NO: 328 Bac437 RRWVIWRR SEQ ID NO: 329 Bac500 PNGKIIWRM SEQ ID NO: 330 Bac501 RRLYMKFKN SEQ ID NO: 331 Bac502 SRNGGASIR SEQ ID NO: 332 Bac503 KWKSIRGHG SEQ ID NO: 333 Bac504 VRRRWIRFW SEQ ID NO: 334 Bac505 RIKIWGGGP SEQ ID NO: 335 Bac506 VKPTRAWRV SEQ ID NO: 336 Bac507 RTKQTTKVR SEQ ID NO: 337 Bac508 KWYRWNNAR SEQ ID NO: 338 Bac509 HYKPNYWKW SEQ ID NO:,339 Bac510 KWSLKHWVV SEQ ID NO: 340 Bac5ll VWVIRGLGK SEQ ID NO: 341 Bac512 GQRVYVRMW SEQ ID NO: 342 Bac513 RYWMRTRPW SEQ ID NO: 343 Bac514 RGTMLRMFQ SEQ ID NO: 344 Bac515 RVGRRHTGK SEQ ID NO: 345 Bac516 VDKYRVRFR SEQ ID NO: 346 Bac517 WSMPLWKRY SEQ ID NO: 347 Bac518 RSIMTQRWW SEQ ID NO: 348 Bac519 RWKPTHHLW SEQ ID NO: 349 Bac520 WQWKVRIWR SEQ ID NO: 350 Bac521 FKGYHWYRR SEQ ID NO: 351 Bac522 KKKIIMMMR SEQ ID NO: 352 Bac523 KRNMGHWMH SEQ ID NO: 353 Bac524 KWSKGVVTN SEQ ID NO: 354 Bac525 WGQTHKSRM SEQ ID NO: 355 Bac526 KHRKWWKRQ SEQ ID NO: 356 Bac527 FYVIWKKGQ SEQ ID NO: 357 Bac528 IQIKYIYKS SEQ ID NO: 358 Bac529 KRNWVGVRG SEQ ID NO: 359 Bac530 YRPWNKGWN SEQ ID NO: 360 Bac531 VKPVRVWKF SEQ ID NO: 361 Bac532 HPQHFRRWR SEQ ID NO: 362 Bac533 KRPHMHHWM SEQ ID NO: 363 Bac534 RKLWRWKRT SEQ ID NO: 364 Bac535 YHQHKGWIR SEQ ID NO: 365 Bac536 PVKRKQRRM SEQ ID NO: 366 Bac537 SRTMQNAMR SEQ ID NO: 367 Bac538 VYKRLQRGL SEQ ID NO: 368 Bac539 TRSVVRKKL SEQ ID NO: 369 Bac540 RAGFVMRMR SEQ ID NO: 370 Bac541 RRYYWKKGV SEQ ID NO: 371 Bac542 WKGRWYKTT SEQ ID NO: 372 Bac543 RWIRVAMRD SEQ ID NO: 373 Bac544 RPRWWAGFY SEQ ID NO: 374 Bac545 WIKWGYRTG SEQ ID NO: 375 Bac546 RNVFQRMAG SEQ ID NO: 376 Bac547 AGRKRVWHK SEQ ID NO: 377 Bac548 MQWGATKIR SEQ ID NO: 378 Bac549 LIMGWQRKP SEQ ID NO: 379 Bac550 ARSWRNPWF SEQ ID NO: 380 Bac551 KVPRPGVMI SEQ ID NO: 381 Bac552 MMWRRIGIK SEQ ID NO: 382 Bac553 VVRKHSLIK SEQ ID NO: 383 Bac554 VWWRGFNRM SEQ ID NO: 384 Bac555 QQRRWWSYV SEQ ID NO: 385 Bac556 RSAQKRGYI SEQ ID NO: 386 Bac557 TRVTRKVTW SEQ ID NO: 387 Bac558 IWSWRWWRM SEQ ID NO: 388 Bac559 KLTRVYRKY SEQ ID NO: 389 Bac560 IKMWRALIR SEQ ID NO: 390 Bac561 RWGKWSWRK SEQ ID NO: 391 Bac562 WKAVRWKKV SEQ ID NO: 392 Bac563 RRIKPVWAW SEQ ID NO: 393 Bac564 SVWMKGRYA SEQ ID NO: 394 Bac565 VSIMARMKW SEQ ID NO: 395 Bac566 RWVGIRVRI SEQ ID NO: 396 Bac567 RIQHKKNGY SEQ ID NO: 397 Bac568 NMGMRWRAK SEQ ID NO: 398 Bac569 RNIQPTRMH SEQ ID NO: 399 Bac570 AKLVSRYKR SEQ ID NO: 400 Bac571 TRRQRHKPQ SEQ ID NO: 401 Bac572 SWMINRYRR SEQ ID NO: 402 Bac573 WYRVIHHYK SEQ ID NO: 403 Bac574 FTMNIRNRM SEQ ID NO: 404 Bac575 WHMSWHKRK SEQ ID NO: 405 Bac576 RLFNSKKYK SEQ ID NO: 406 Bac577 WKQNVGKY SEQ ID NO: 407 Bac578 KMKEGAKGF SEQ ID NO: 408 Bac579 VWGIRKNSS SEQ ID NO: 409 Bac580 RGIAVIKMV SEQ ID NO: 410 Bac581 YVIIGRGRR SEQ ID NO: 411 Bac582 RVKKLRIQP SEQ ID NO: 412 Bac583 KQWSGIKNT SEQ ID NO: 413 Bac584 KRRWMWVKR SEQ ID NO: 414 Bac585 PHKWNFSKY SEQ ID NO: 415 Bac586 FGRWPKLFR SEQ ID NO: 416 Bac587 KVYRRHAGY SEQ ID NO: 417 Bac588 TYWRRTGPY SEQ ID NO: 418 Bac589 KRSKPKYKA SEQ ID NO: 419 Bac590 MIRRWKKQW SEQ ID NO: 420 Bac591 HQRSRLWHK SEQ ID NO: 421 Bac592 WNIFVKGWR SEQ ID NO: 422 Bac593 PKTRKKGLY SEQ ID NO: 423 Bac594 RSNKGHWYV SEQ ID NO: 424 Bac595 MRIWRHWRK SEQ ID NO: 425 Bac596 IRGRWKKLR SEQ ID NO: 426 Bac597 VKKVRKGIV SEQ ID NO: 427 Bac598 MGFFRRRPN SEQ ID NO: 428 Bac599 MMKGFMGRW SEQ ID NO: 429 Bac600 GRRRLVWTR SEQ ID NO: 430 Bac601 VAKRTKAYW SEQ ID NO: 431 Bac602 KYKQRVQHI SEQ ID NO: 432 Bac603 KKRTYKYPF SEQ ID NO: 433 Bac604 FRWKWVKHI SEQ ID NO: 434 Bac605 KWRWRVKKR SEQ ID NO: 435 Bac606 IIIWGLRRA SEQ ID NO: 436 Bac607 NIARRKGFR SEQ ID NO: 437 Bac608 SHMHLRKVR SEQ ID NO: 438 Bac609 RIGAGNKQG SEQ ID NO: 439 Bac610 GGHLRWKNA SEQ ID NO: 440 Bac6ll RINKVVPRV SEQ ID NO: 441 Bac612 WSPRKKQKI SEQ ID NO: 442 Bac613 VYSRYMKGG SEQ ID NO: 443 Bac614 GKMWRNNYL SEQ ID NO: 444 Bac615 KRHWHNSIW SEQ ID NO: 445 Bac616 PWTTKNFWR SEQ ID NO: 446 Bac617 FPNAVHRRR SEQ ID NO: 447 Bac618 PFRAGNTKR SEQ ID NO: 448 Bac619 WGRISKRMR SEQ ID NO: 449 Bac620 GWRKVRVVV SEQ ID NO: 450 Bac621 WGKIVGKGR SEQ ID NO: 451 Bac622 MWPGARGAR SEQ ID NO: 452 Bac623 IAGRNIWPR SEQ ID NO: 453 Bac624 VRTMVKVPM SEQ ID NO: 454 Bac625 HKRGWRKGA SEQ ID NO: 455 Bac626 SGRWHSKFW SEQ ID NO: 456 Bac627 ITWTKIKKF SEQ ID NO: 457 Bac628 KRSLMKMWP SEQ ID NO: 458 Bac629 VWSRYNKPR SEQ ID NO: 459 Bac630 PHVKKGGVA SEQ ID NO: 460 Bac631 AYGGTKMRV SEQ ID NO: 461 Bac632 HPVKWRRKK SEQ ID NO: 462 Bac633 RWVRFVMGI SEQ ID NO: 463 Bac634 SIVQKGWFR SEQ ID NO: 464 Bac635 NSKTHGFRY SEQ ID NO: 465 Bac636 RVVRSARGI SEQ ID NO: 466 Bac637 LGKNKATKT SEQ ID NO: 467 Bac638 KGFPKSMSG SEQ ID NO: 468 Bac639 GKKFWNFWG SEQ ID NO: 469 Bac640 MKMKPRKVS SEQ ID NO: 470 Bac641 RNVRNNNTR SEQ ID NO: 471 Bac642 WRGKPKGLF SEQ ID NO: 472 Bac643 KIRNRKIKW SEQ ID NO: 473 Bac644 RRRRARGHW SEQ ID NO: 474 Bac645 GNMFQWRKG SEQ ID NO: 475 Bac646 VRISIMRWW SEQ ID NO: 476 Bac647 RVRHGFKWW SEQ ID NO: 477 Bac648 WKWKWSKWI SEQ ID NO: 478 Bac649 GKNVMMGRI SEQ ID NO: 479 Bac650 YWKVKTKHH SEQ ID NO: 480 Bac651 IKQWMRRKN SEQ ID NO: 481 Bac652 HKKNPWNGK SEQ ID NO: 482 Bac653 KRSRIRIGV SEQ ID NO: 483 Bac654 QGKWQRPRM SEQ ID NO: 484 Bac655 QRSTQRSWW SEQ ID NO: 485 Bac656 NRSMRRKPR SEQ ID NO: 486 Bac657 HWKRISWGR SEQ ID NO: 487 Bac658 RRRWFRTRG SEQ ID NO: 488 Bac659 VKSPKWWIG SEQ ID NO: 489 Bac660 RIWVWRHKY SEQ ID NO: 490 Bac661 WVRPRGFWS SEQ ID NO: 491 Bac662 LRSRGSGVH SEQ ID NO: 492 Bac663 FHRWWYFFK SEQ ID NO: 493 Bac664 RGVFKAMST SEQ ID NO: 494 Bac665 WRGGWTHRR SEQ ID NO: 495 Bac666 SRMKFWVIK SEQ ID NO: 496 Bac667 YMTNRKVSG SEQ ID NO: 497 Bac668 WQIGKIWRT SEQ ID NO: 498 Bac669 RQVKYINHY SEQ ID NO: 499 Bac670 FMWRVIKMI SEQ ID NO: 500 Bac671 FDRAGRKLI SEQ ID NO: 501 Bac672 VKRVKWWWS SEQ ID NO: 502 Bac673 RVVFRSQPF SEQ ID NO: 503 Bac674 RVKVWSKKF SEQ ID NO: 504 Bac675 NAMWKYVWR SEQ ID NO: 505 Bac676 RTQQSRPSV SEQ ID NO: 506 Bac677 VRYIGAIYR SEQ ID NO: 507 Bac678 SIRKWIFWI SEQ ID NO: 508 Bac679 NKIVTLPKL SEQ ID NO: 509 Bac680 IMARVFPRW SEQ ID NO: 510 Bac681 TIRKKWKGS SEQ ID NO: 511 Bac682 RRIEKSLRW SEQ ID NO: 512 Bac683 RWKSRGRTL SEQ ID NO: 513 Bac684 EGNIRKRVY SEQ ID NO: 514 Bac685 ILKSFQRGH SEQ ID NO: 515 Bac686 GINFKHKRF SEQ ID NO: 516 Bac687 KNMRLSNWQ SEQ ID NO: 517 Bac688 GRNFKVPVR SEQ ID NO: 518 Bac689 IKKKFKWNT SEQ ID NO: 519 Bac690 DRRRVQKGL SEQ ID NO: 520 Bac691 GQRGRPWAT SEQ ID NO: 521 Bac692 HRKNKKHYM SEQ ID NO: 522 Bac693 INPGTAGKK SEQ ID NO: 523 Bac694 KFIVVKRVV SEQ ID NO: 524 Bac695 RHKTWYPGK SEQ ID NO: 525 Bac696 RPLRKKVKL SEQ ID NO: 526 Bac697 SKRWILVRR SEQ ID NO: 527 Bac698 TKRWQTKFM SEQ ID NO: 528 Bac699 WPKTRTVAK SEQ ID NO: 529 Bac700 FKPVRIVFS SEQ ID NO: 530 Bac701 MRVITVRIL SEQ ID NO: 531 Bac702 RHWQQKVRS SEQ ID NO: 532 Bac703 NQAKKKVGA SEQ ID NO: 533 Bac704 MKYQGKGMQ SEQ ID NO: 534 Bac705 RGWPRNWPT SEQ ID NO: 535 Bac706 LKISGYVKH SEQ ID NO: 536 Bac707 RWKLFKVWW SEQ ID NO: 537 Bac708 RRANFFFSV SEQ ID NO: 538 Bac709 RYNWYGQLR SEQ ID NO: 539 Bac7lO RGFWMKRWW SEQ ID NO: 540 Bac7ll GGGRRSQWK SEQ ID NO: 541 Bac712 WYGFKRKIV SEQ ID NO: 542 Bac713 WSAIRKKGK SEQ ID NO: 543 Bac714 HRQPWRGRI SEQ ID NO: 544 Bac715 KNMVTKWNK SEQ ID NO: 545 Bac716 HIRGRFWRW SEQ ID NO: 546 Bac717 IIPPKWYRS SEQ ID NO: 547 Bac718 IPRQWWTFK SEQ ID NO: 548 Bac719 WSNIIRKFM SEQ ID NO: 549 Bac720 RVTYRRNVT SEQ ID NO: 550 Bac721 KWWRIRGWI SEQ ID NO: 551 Bac722 VEKHIRQRV SEQ ID NO: 552 Bac723 RISSVPRMP SEQ ID NO: 553 Bac724 ANNPLRVRL SEQ ID NO: 554 Bac725 QRWIRIKPW SEQ ID NO: 555 Bac726 RGWPRQIYY SEQ ID NO: 556 Bac727 VKLGLGYQR SEQ ID NO: 557 Bac728 VHQLKKRHW SEQ ID NO: 558 Bac729 RWWQVRMYI SEQ ID NO: 559 Bac730 IVLRNIKFI SEQ ID NO: 560 Bac731 VRTRHWSPS SEQ ID NO: 561 Bac732 WFRWHNRLV SEQ ID NO: 562 Bac733 NRLWRYGRL SEQ ID NO: 563 Bac734 HPWNRYKWG SEQ ID NO: 564 Bac735 QVRVRRRII SEQ ID NO: 565 Bac736 VRRRPSMFM SEQ ID NO: 566 Bac737 RKYQIGRHI SEQ ID NO: 567 Bac738 AKRRSRMKR SEQ ID NO: 568 Bac739 KLWWMIRRW SEQ ID NO: 569 Bac740 HNLHDIKRK SEQ ID NO: 570 Bac741 RGVGVTFKL SEQ ID NO: 571 Bac742 VPKLHYVVR SEQ ID NO: 572 Bac743 VHWRGAKVT SEQ ID NO: 573 Bac744 NGRWRFWSG SEQ ID NO: 574 Bac745 KPVHWKKLQ SEQ ID NO: 575 Bac746 KRNRGGWKV SEQ ID NO: 576 Bac747 TRNKTGYWW SEQ ID NO: 577 Bac748 YQQRLRHIY SEQ ID NO: 578 Bac749 GVVVWRRRV SEQ ID NO: 579 Bac750 IMTRWKMHT SEQ ID NO: 580 Bac751 TVHKRAAYP SEQ ID NO: 581 Bac752 VKHKRGFYR SEQ ID NO: 582 Bac753 RWTISFKRS SEQ ID NO: 583 Bac754 GRMRHKRFT SEQ ID NO: 584 Bac755 HSKSVLWIK SEQ ID NO: 585 Bac756 KQMGRRISG SEQ ID NO: 586 Bac757 RRMHSKIKG SEQ ID NO: 587 Bac758 RINPKIYRS SEQ ID NO: 588 Bac759 TIKRYIWIK SEQ ID NO: 589 Bac760 WLIRPGAKL SEQ ID NO: 590 Bac761 NTFRRAWRM SEQ ID NO: 591 Bac762 KTRARWKNK SEQ ID NO: 592 Bac763 HRPKIGFAG SEQ ID NO: 593 Bac764 MSHKMRQKR SEQ ID NO: 594 Bac765 FRGRWPLAR SEQ ID NO: 595 Bac766 VIKQVGPHK SEQ ID NO: 596 Bac767 AGFKRMWRV SEQ ID NO: 597 Bac768 YRAVNKNPI SEQ ID NO: 598 Bac769 AIWIPSKWR SEQ ID NO: 599 Bac770 KNGAWWVLR SEQ ID NO: 600 Bac771 MKMKRRMGV SEQ ID NO: 601 Bac772 RTIKRVV WWW SEQ ID NO: 602 Bac773 AWYKKKRWW SEQ ID NO: 603 Bac774 PRVLSRLIK SEQ ID NO: 604 Bac775 WMFPKATRV SEQ ID NO: 605 Bac776 MQVSKVKQI SEQ ID NO: 606 Bac777 SWKRINQIN SEQ ID NO: 607 Bac778 NRWRLINAQ SEQ ID NO: 608 Bac779 RPSWHKWHH SEQ ID NO: 609 Bac780 RVPINKWHR SEQ ID NO: 610 Bac781 ILKIVRIKR SEQ ID NO: 611 Bac782 DVWWKRLPR SEQ ID NO: 612 Bac783 WIYWKVRGG SEQ ID NO: 613 Bac784 HHRPPFRFQ SEQ ID NO: 614 Bac785 MQRNFRRSI SEQ ID NO: 615 Bac786 LMVRVLKNR SEQ ID NO: 616 Bac787 HKWTQKYKA SEQ ID NO: 617 Bac788 LWRRKWRTG SEQ ID NO: 618 Bac789 KYVRRWKSG SEQ ID NO: 619 Bac790 VAGWWSRRM SEQ ID NO: 620 Bac791 IRQRWIWWY SEQ ID NO: 621 Bac792 FRVRRWVRM SEQ ID NO: 622 Bac793 FVMFLRQFK SEQ ID NO: 623 Bac794 RNFVPRMIG SEQ ID NO: 624 Bac795 RPTRQKNMN SEQ ID NO: 625 Bac796 RRYIKWHIV SEQ ID NO: 626 Bac797 WGKMNVRIH SEQ ID NO: 627 Bac798 KITFRRYNP SEQ ID NO: 628 Bac799 QAQQWWFKR SEQ ID NO: 629 Bac800 IKSMFWRGP SEQ ID NO: 630 Bac801 QPMRGIRMT SEQ ID NO: 631 Bac802 HMILIRLFR SEQ ID NO: 632 Bac803 SMNAPRVKR SEQ ID NO: 633 Bac804 WKSKLSVNK SEQ ID NO: 634 Bac805 ISNMRVSAK SEQ ID NO: 635 Bac806 VRMGWWAHR SEQ ID NO: 636 Bac807 RWPRVSWQA SEQ ID NO: 637 Bac808 LSRTGVTRG SEQ ID NO: 638 Bac809 RQLKPQNWS SEQ ID NO: 639 Bac8lO LHVRHKQHM SEQ ID NO: 640 Bac8ll QFRKIKAVS SEQ ID NO: 641 Bac812 HWFNGNKKK SEQ ID NO: 642 Bac813 RRVKIVRKI SEQ ID NO: 643 Bac814 SMGKRTVWMR SEQ ID NO: 644 Bac815 KYSWVKKNI SEQ ID NO: 645 Bac816 FPIRFKIWI SEQ ID NO: 646 Bac817 KFFTYSRFR SEQ ID NO: 647 Bac818 LGRKRMGHW SEQ ID NO: 648 Bac819 NWRKLYRRK SEQ ID NO: 649 Bac820 RGKIVVATL SEQ ID NO: 650 Bac821 GWRRPGHNK SEQ ID NO: 651 Bac822 IIAGTGLKR SEQ ID NO: 652 Bac823 RRMKRRSIM SEQ ID NO: 653 Bac824 KVFGRRYRK SEQ ID NO: 654 Bac825 LQMFWYLRR SEQ ID NO: 655 Bac826 RAYHKMRKK SEQ ID NO: 656 Bac827 NPARWRPRV SEQ ID NO: 657 Bac828 YVGKDRRKP SEQ ID NO: 658 Bac829 LRWWTNTRW SEQ ID NO: 659 Bac830 MYKQMMRVG SEQ ID NO: 660 Bac831 PRRPWMRHR SEQ ID NO: 661 Bac832 LNKFVKQRR SEQ ID NO: 662 Bac833 ITINSRKWT SEQ ID NO: 663 Bac834 RQFGMRKWT SEQ ID NO: 664 Bac835 RIAVRHWHM SEQ ID NO: 665 Bac836 HAVSQHRGK SEQ ID NO: 666 Bac837 KSMYFRRSM SEQ ID NO: 667 Bac838 VGTIRLGRG SEQ ID NO: 668 Bac839 MRVGMRTKF SEQ ID NO: 669 Bac840 LRRIWRMWS SEQ ID NO: 670 Bac841 RFHRRAMFR SEQ ID NO: 671 Bac842 MRPRHYIKN SEQ ID NO: 672 Bac843 MRKRMKVYS SEQ ID NO: 673 Bac844 MKHRHFGII SEQ ID NO: 674 Bac845 VRGKVYAWW SEQ ID NO: 675 Bac846 KIRLIRGKI SEQ ID NO: 676 Bac847 KWINGPRKA SEQ ID NO: 677 Bac848 GKNRITYSK SEQ ID NO: 678 Bac849 GRAKRQHVI SEQ ID NO: 679 Bac850 GIRFTRWLK SEQ ID NO: 680 Bac851 AKMAWYKNP SEQ ID NO: 681 Bac852 TRAKYIILR SEQ ID NO: 682 Bac853 RSIVRWFGR SEQ ID NO: 683 Bac854 RSEYKQIYR SEQ ID NO: 684 Bac855 KRRMRWIIM SEQ ID NO: 685 Bac856 YTKRWPVFR SEQ ID NO: 686 Bac857 PYVSRWYKK SEQ ID NO: 687 Bac858 RRFIKWGHV SEQ ID NO: 688 Bac859 YVHKRKSMW SEQ ID NO: 689 Bac860 QIGYIYRVR SEQ ID NO: 690 Bac861 ARHWKMLWY SEQ ID NO: 691 Bac862 VAVKKKRIS SEQ ID NO: 692 Bac863 RKYGRSVPH SEQ ID NO: 693 Bac864 TTGRGKIKR SEQ ID NO: 694 Bac865 VWTIHTKMK SEQ ID NO: 695 Bac866 RRWQEKGWR SEQ ID NO: 696 Bac867 RQSGTFFKW SEQ ID NO: 697 Bac868 WRITRGGII SEQ ID NO: 698 Bac869 VAGRYKMQA SEQ ID NO: 699 Bac870 KRGTHMRNV SEQ ID NO: 700 Bac871 IGYHKIPMR SEQ ID NO: 701 Bac872 YRFWGKKGF SEQ ID NO: 702 Bac873 HYKRRGSRW SEQ ID NO: 703 Bac874 GAKGGQIVR SEQ ID NO: 704 Bac875 MIIIRSRRV SEQ ID NO: 705 Bac876 NLGAWYKWK SEQ ID NO: 706 Bac877 GPRVRKIWS SEQ ID NO: 707 Bac878 RGISTYHKR SEQ ID NO: 708 Bac879 IRAIKKVRK SEQ ID NO: 709 Bac880 FGYRIKKRN SEQ ID NO: 710 Bac881 PKNYMKIFP SEQ ID NO: 711 Bac882 QAAQKKKRS SEQ ID NO: 712 Bac883 MFGIPRHMR SEQ ID NO: 713 Bac884 HAGVGIRHR SEQ ID NO: 714 Bac885 LKWQAKSWI SEQ ID NO: 715 Bac886 RYRRKRRWA SEQ ID NO: 716 Bac887 LRGLVLKSG SEQ ID NO: 717 Bac888 RRRKIHGPW SEQ ID NO: 718 Bac889 RTARGGKFK SEQ ID NO: 719 Bac890 MGNKIVWKN SEQ ID NO: 720 Bac891 WRITIIKIT SEQ ID NO: 721 Bac892 FRWRVSGRW SEQ ID NO: 722 Bac893 TRVIPRMYY SEQ ID NO: 723 Bac894 KKQARKYIK SEQ ID NO: 724 Bac895 WIYIARSVK SEQ ID NO: 725 Bac896 RVFTLARHV SEQ ID NO: 726 Bac897 NYIVYRRVF SEQ ID NO: 727 Bac898 NRFSKKHWK SEQ ID NO: 728 Bac899 NSRGWQRRW SEQ ID NO: 729 Bac900 TSSGNRKVT SEQ ID NO: 730 Bac901 WIKAGWRSW SEQ II) NO: 731 Bac902 TWIRLSRRV SEQ ID NO: 732 Bac903 IRKWWVRNV SEQ ID NO: 733 Bac904 YKKPPWQFK SEQ ID NO: 734 Bac905 QQSILRKNN SEQ ID NO: 735 Bac906 GHKFWKINR SEQ ID NO: 736 Bac907 RVRWYRIFY SEQ ID NO: 737 Bac908 WWRVVYKGV SEQ ID NO: 738 Bac909 SKGIIAKWW SEQ ID NO: 739 Bac9lO QIKKQFVKQ SEQ ID NO: 740 Bac9ll KGTVNFYRQ SEQ ID NO: 741 Bac912 LMMRHYWIR SEQ ID NO: 742 Bac913 WWNRRKVDQ SEQ ID NO: 743 Bac914 RYRIRKKRG SEQ ID NO: 744 Bac915 KRQMHIHSR SEQ ID NO: 745 Bac916 HKSMLRIWG SEQ ID NO: 746 Bac917 WKILIIFGR SEQ ID NO: 747 Bac918 KKVSLHREA SEQ ID NO: 748 Bac919 PLSRVRNRW SEQ ID NO: 749 Bac920 GWSHRVKGI SEQ ID NO: 750 Bac921 RTIRRNWIE SEQ ID NO: 751 Bac922 ITMPSKRRV SEQ ID NO: 752 Bac923 KRKPPVHQK SEQ ID NO: 753 Bac924 IWPKHRSKW SEQ ID NO: 754 Bac925 QKAFWMWWR SEQ ID NO: 755 Bac926 WRQHWGRHR SEQ ID NO: 756 Bac927 VMGKARFWR SEQ ID NO: 757 Bac928 WIVVKKQNR SEQ ID NO: 758 Bac929 PRYQGWWRV SEQ ID NO: 759 Bac930 KMRRPNIWL SEQ ID NO: 760 Bac931 GGKRVFVRS SEQ ID NO: 761 Bac932 GRGHPKYVT SEQ ID NO: 762 Bac933 KAARNWKVW SEQ ID NO: 763 Bac934 KKMSWGHTR SEQ ID NO: 764 Bac935 KKTYWYNRA SEQ ID NO: 765 Bac936 KNRRRRFWF SEQ ID NO: 766 Bac937 RRRQKRGVW SEQ ID NO: 767 Bac938 GRRNHQRAK SEQ ID NO: 768 Bac939 QKMGHRWRI SEQ ID NO: 769 Bac940 PKWKIQKGH SEQ ID NO: 770 Bac941 AMRRFMRRP SEQ ID NO: 771 Bac942 GKGMGRRAW SEQ ID NO: 772 Bac943 HKRRKAKIM SEQ ID NO: 773 Bac944 IMMNHRKWQ SEQ ID NO: 774 Bac945 RWMRMKWVT SEQ ID NO: 775 Bac946 RWGYRYNFI SEQ ID NO: 776 Bac947 MWKKNNWNL SEQ ID NO: 777 Bac948 WKRVGRKRL SEQ ID NO: 778 Bac949 WLHGVKKMW SEQ ID NO: 779 Bac950 EYWNWKRKV SEQ ID NO: 780 Bac951 TKVTRGWPW SEQ ID NO: 781 Bac952 QRWIQNTRW SEQ ID NO: 782 Bac953 GKYIFKWWQ SEQ ID NO: 783 Bac954 IVWKLRFQP SEQ ID NO: 784 Bac955 WWAVNRNRK SEQ ID NO: 785 Bac956 SIRMTKGKM SEQ ID NO: 786 Bac957 NIKWGFFGK SEQ ID NO: 787 Bac958 WMRQWRHWY SEQ ID NO: 788 Bac959 PKVKRIWPK SEQ ID NO: 789 Bac960 RRRKIAHKM SEQ ID NO: 790 Bac961 RKYIKYVWN SEQ ID NO: 791 Bac962 QPKRYVQTP SEQ ID NO: 792 Bac963 LVGNPKWGR SEQ ID NO: 793 Bac964 YKRAYSPIS SEQ ID NO: 794 Bac965 KHKWGTFRF SEQ ID NO: 795 Bac966 KIFLKYKGW SEQ ID NO: 796 Bac967 RNVRHHWFR SEQ ID NO: 797 Bac968 VIAVKRHLG SEQ ID NO: 798 Bac969 RWKVGILRR SEQ ID NO: 799 Bac970 WIQGIKMVR SEQ ID NO: 800 Bac971 GWFKVTYKK SEQ ID NO: 801 Bac972 YVMTKWRYV SEQ ID NO: 802 Bac973 PRIFWKHIN SEQ ID NO: 803 Bac974 VSPRWIWLK SEQ ID NO: 804 Bac975 WVAIPGRSR SEQ ID NO: 805 Bac976 NGFRKWWSR SEQ ID NO: 806 Bac977 QFYIMKRYY SEQ ID NO: 807 Bac978 ARHGRKTKK SEQ ID NO: 808 Bac979 KRGRAKHIK SEQ ID NO: 809 Bac980 NLWKIKTPI SEQ ID NO: 810 Bac981 VPKGWKFLS SEQ ID NO: 811 Bac982 RFMKEWFAK SEQ ID NO: 812 Bac983 MGARKWIWW SEQ ID NO: 813 Bac984 GLNHRRRPI SEQ ID NO: 814 Bac985 VLMRKRIWH SEQ ID NO: 815 Bac986 PGPYKKRQF SEQ ID NO: 816 Bac987 WKYLYKPNP SEQ ID NO: 817 Bac988 RKMRWWIRR SEQ ID NO: 818 Bac989 AWRNSFRRG SEQ ID NO: 819 Bac990 WKVGIIRAG SEQ ID NO: 820 Bac991 WGRKTHYWH SEQ ID NO: 821 Bac992 RIQHRYFLM SEQ ID NO: 822 Bac993 FSWKVRIGV SEQ ID NO: 823 Bac994 MPTKYGRHR SEQ ID NO: 824 Bac995 RSPWRHRQF SEQ ID NO: 825 Bac996 KRIWHIWRW SEQ ID NO: 826 Bac997 KVVWLHRWQ SEQ ID NO: 827 Bac998 IYRRKMIFQ SEQ ID NO: 828 Bac999 HRYQYWKLT SEQ ID NO: 829 Bac1000 AYKYFSQKR SEQ ID NO: 830 BaclOOl KLVHKVTMT SEQ ID NO: 831 Bac1002 VRNRRFIWR SEQ ID NO: 832 Bac1003 RVLLVARPN SEQ ID NO: 833 Bac1004 YKKHLRWGL SEQ ID NO: 834 Bac1005 RKVYSARPG SEQ ID NO: 835 Bacl006 QVMRWVQKL SEQ ID NO: 836 Bac1007 IKILVLRVI SEQ ID NO: 837 BaclOO8 WHKRYFRSP SEQ ID NO: 838 Bac1009 KMGNAKWRH SEQ ID NO: 839 BaclOlO FGHHRFRLA SEQ ID NO: 840 Bac10l1 GHPSKIVRR SEQ ID NO: 841 Bac1012 WRVWVRVKR SEQ ID NO: 842 Bac1013 RSMTLWRKH SEQ ID NO: 843 Bacl014 IRLYITRWL SEQ ID NO: 844 Bacl015 IVKMRRRHA SEQ ID NO: 845 Bacl016 FWRRQRWKQ SEQ ID NO: 846 Bac1017 QQMYSRQRK SEQ ID NO: 847 Bacl018 KPMKTWAKG SEQ ID NO: 848 Bacl019 KYFVTKWGT SEQ ID NO: 849 Bac1020 IRRKGTKRR SEQ ID NO: 850 Bacl021 GMRHFKWGI SEQ ID NO: 851 Bac1022 KKQVAIVRT SEQ ID NO: 852 Bac1023 NGFKYVRSM SEQ ID NO: 853 Bac1024 LWVGRLVYK SEQ ID NO: 854 Bac1025 RWVNKITWI SEQ ID NO: 855 Bac1026 AARIFRRYS SEQ ID NO: 856 Bac1027 SQRWPTRGR SEQ ID NO: 857 Bac1028 IRAKRWRQI SEQ ID NO: 858 Bac1029 VKKPGWRLY SEQ ID NO: 859 Bacl030 KRKTKLNPA SEQ ID NO: 860 Bacl031 HVKGWTKFR SEQ ID NO: 861 Bac1032 RPPVFHKHN SEQ ID NO: 862 Bac1033 NVMTMRLKK SEQ ID NO: 863 Bac1034 QWIKIRFSR SEQ ID NO: 864 Bac1035 WYRRWSNVR SEQ ID NO: 865 Bac1036 VFARRIWGI SEQ ID NO: 866 Bac1037 HFTRPKFWR SEQ ID NO: 867 Bac1038 WVQVKMASK SEQ ID NO: 868 Bac1039 SWRSVKKVN SEQ ID NO: 869 Bac1040 WYYVRYRWW SEQ ID NO: 870 Bacl041 MHDRKWAVR SEQ ID NO: 871 Bac1042 GGKGGRYRG SEQ ID NO: 872 Bac1043 YVTYKTWRS SEQ ID NO: 873 Bac1044 QRRNNQRVV SEQ ID NO: 874 Bac1045 WRWVFMIVR SEQ ID NO: 875 Bac1046 FYSMTYIRK SEQ ID NO: 876 Bac1047 HPKKMAVVR SEQ ID NO: 877 Bac1048 YRLTRYKGA SEQ ID NO: 878 Bac1049 VKARFRIQW SEQ ID NO: 879 Bac1050 IRRAKLRGR SEQ ID NO: 880 Bac1051 KGINIKWKP SEQ ID NO: 881 Bac1052 LWKYLRHGV SEQ ID NO: 882 Bac1053 THAMWKGKN SEQ ID NO: 883 Bac1054 IKKIHYRNK SEQ ID NO: 884 Bac1055 RIMGWVHIK SEQ ID NO: 885 Bac1056 KIRHIWIVG SEQ ID NO: 886 Bac1057 PRQLFWPRW SEQ ID NO: 887 Bac1058 SHARWMKIH SEQ ID NO: 888 Bac1059 KISKKIKVV SEQ ID NO: 889 Bacl060 HGKVVGQRI SEQ ID NO: 890 Bacl061 RQVIWRWIT SEQ ID NO: 891 Bac1062 TKIRARRVL SEQ ID NO: 892 Bac1063 YRRVRQRDY SEQ ID NO: 893 Bac1064 YKRKIVIWYIW SEQ ID NO: 894 Bac1065 WKYGGPRQR SEQ ID NO: 895 Bac1066 ATWPHGKKV SEQ ID NO: 896 Bac1067 RGGKHRKKA SEQ ID NO: 897 Bac1068 WKRWIRVMQ SEQ ID NO: 898 Bac1069 WIIKEVRKP SEQ ID NO: 899 Bacl070 YRQIlVIRWVQ SEQ ID NO: 900 Bac1071 FKRRGGWLR SEQ ID NO: 901 Bac1072 IVWNNSRVR SEQ ID NO: 902 Bac1073 RRGGYVMYV SEQ ID NO: 903 Bac1074 TSVKMFWRA SEQ ID NO: 904 Bac1075 KHIWWKLHM SEQ ID NO: 905 Bac1076 RLWGIIRKT SEQ ID NO: 906 Bac1077 MVRPNRIRR SEQ ID NO: 907 Bac1078 WPRAKNPSA SEQ ID NO: 908 Bac1079 RRWLRAIIY SEQ ID NO: 909 BaclO8O IGNRRNTGI SEQ ID NO: 910 Bac1081 YIRSLIGKP SEQ ID NO: 911 Bac1082 TGGWNIRMR SEQ ID NO: 912 Bac1083 VVAVNKERK SEQ ID NO: 913 Bac1084 NAHNKRYYR SEQ ID NO: 914 Bac1085 WWRIAFKLT SEQ ID NO: 915 Bac1086 NGQRKYIYI SEQ ID NO: 916 Bac1087 RGWGWRRLY SEQ ID NO: 917 Bac1088 RIAFPMKGG SEQ ID NO: 918 Bac1089 RAKNVLGTY SEQ ID NO: 919 Bac1090 NRRIKGQWV SEQ ID NO: 920 Bac1091 RTSWMNRIW SEQ ID NO: 921 Bac1092 TWIKQLINK SEQ ID NO: 922 Bac1093 QKRKPRWPW SEQ ID NO: 923 Bac1094 SKLLVRMWK SEQ ID NO: 924 Bac1095 YKQGWWKWL SEQ ID NO: 925 Bac1096 TWAPRHKSQ SEQ ID NO: 926 Bac1097 KWVRTGYQW SEQ ID NO: 927 Bac1098 QARRKQVWI SEQ ID NO: 928 Bac1099 WKIGRIKMR SEQ ID NO: 929 Bac1100 FIIRGRWAN SEQ ID NO: 930 Bac1101 MLRKMGAPQ SEQ ID NO: 931 Bac1102 KRRPVKSYK SEQ ID NO: 932 Bacl103 IYWVNFRLR SEQ ID NO: 933 Bac1104 MRIRKWQLS SEQ ID NO: 934 Bac1105 WGRKQKQWS SEQ ID NO: 935 Bac1106 RNWWTGHWR SEQ ID NO: 936 Bacl107 VGRQQRYMK SEQ ID NO: 937 Bac1108 GRKRNVEGR SEQ ID NO: 938 Bac1109 ALGRIRGKR SEQ ID NO: 939 Baclll0 MNKWINKLM SEQ ID NO: 940 Bacllll PKRWWGIRN SEQ ID NO: 941 Bac1112 RHYRYTGII SEQ ID NO: 942 Baclll3 PVRRWGWTL SEQ ID NO: 943 Bac11l4 RIVSGWGWR SEQ ID NO: 944 Bac1115 RIKLLTIWK SEQ ID NO: 945 Bac1116 KWVKNWRYR SEQ ID NO: 946 Bacl117 YQKGVRVIT SEQ ID NO: 947 Bac1118 VRGGAKGGS SEQ ID NO: 948 Bac1119 AIWGRIRKR SEQ ID NO: 949 Bac1120 RIWKTATFG SEQ ID NO: 950 Bac1121 HISRGARHK SEQ ID NO: 951 Bac1122 YVTRKMIHQ SEQ ID NO: 952 Bac1123 LMIRVGWRW SEQ ID NO: 953 Bac1124 WSQYMFKRW SEQ ID NO: 954 Bac1125 RNIITYRFQ SEQ ID NO: 955 Bac1126 KWRWAKGRQ SEQ ID NO: 956 Bac1127 PGRTKIHRG SEQ ID NO: 957 Bac1128 MNVYARLRH SEQ ID NO: 958 Bac1129 WFNYKRHVL SEQ ID NO: 959 Bac1130 RQMRSIRGR SEQ ID NO: 960 B ac 1 l31 RGFRKIYKR SEQ ID NO: 961 Baci132 YSGPIRQAR SEQ ID NO: 962 Bac1133 IVATVWRKN SEQ ID NO: 963 Bac1134 WGKRYPKYW SEQ ID NO: 964 Bac1135 ITWPRGGGK SEQ ID NO: 965 Bac1136 WKFKKIGMQ SEQ ID NO: 966 Bac1137 RQGRIWWVR SEQ ID NO: 967 Bac1138 YMKAFVSRW SEQ ID NO: 968 Bac1139 MHAKVRIGL SEQ ID NO: 969 Bac1140 YHVRSKWGW SEQ ID NO: 970 Bac1141 ITAAKIKQK SEQ ID NO: 971 Bac1142 LNYSRIHTR SEQ ID NO: 972 Bac1143 WVQKRKKGR SEQ ID NO: 973 Bac1144 WQAIRRIVG SEQ ID NO: 974 Bac1145 RRLITWLVP SEQ ID NO: 975 Bac1146 KVKRQNKKR SEQ ID NO: 976 Bac1147 WSKTHIRRN SEQ ID NO: 977 Bac1148 LQVKWWVKF SEQ ID NO: 978 Bac1149 RKDNKKVVV SEQ ID NO: 979 Bac1150 VRPWRGRIL SEQ ID NO: 980 Bac1151 KWRAAQWVL SEQ ID NO: 981 Bac1152 IKAGRGMVR SEQ ID NO: 982 Bac1153 KIRLKVWRA SEQ ID NO: 983 Bac1154 HWWLRPIVR SEQ ID NO: 984 Bac1155 GMYNKRFKR SEQ ID NO: 985 Bac1156 RLQIWTRGW SEQ ID NO: 986 Bac1157 KTGLKSKVR SEQ ID NO: 987 Bac1158 RKQQVWRIQ SEQ ID NO: 988 Bac1159 LGKRGKHRW SEQ ID NO: 989 Bac1160 GLRHGNYRW SEQ ID NO: 990 Bac1161 RVRRMTRWM SEQ ID NO: 991 Bac1162 KLARWTRGG SEQ ID NO: 992 Bac1163 VVRKRYVRI SEQ ID NO: 993 Bac1164 VHRYMPFGR SEQ ID NO: 994 Bac1165 KITHTFRPR SEQ ID NO: 995 Bac1166 ARRPAQWIQ SEQ ID NO: 996 Bac1167 RVSSGKLTH SEQ ID NO: 997 Bac1168 RWRTGPSIP SEQ ID NO: 998 Bac1169 LRLRRYKKW SEQ ID NO: 999 Bac1170 AKMTWIFRP SEQ ID NO: 1000 Bac1171 ARWKRMWML SEQ ID NO: 1001 Bac1172 GRRVAVHRR SEQ ID NO: 1002 Bac1173 RRWWFPFYA SEQ ID NO: 1003 Bac1174 KHHKGVWWA SEQ ID NO: 1004 Bac1175 LLYWKRGIY SEQ ID NO: 1005 Bac1176 PVNYRKKRP SEQ ID NO: 1006 Bac1177 LRGGTGIFR SEQ ID NO: 1007 Bac1178 HHGRFRHWW SEQ ID NO: 1008 Bac1179 TNRHQQKRW SEQ ID NO: 1009 Bac1180 VQQLTKWSK SEQ ID NO: 1010 Bac1181 RRRPGQKKW SEQ ID NO: 1011 Bac1182 RPGSWRWRV SEQ ID NO: 1012 Bac1183 PRLWNRRQR SEQ ID NO: 1013 Bac1184 RWIVWSRGK SEQ ID NO: 1014 Bac1185 SPHLGWKRS SEQ ID NO: 1015 Bac1186 NRRWQWRMI SEQ ID NO: 1016 Bac1187 WPRRGYMVA SEQ ID NO: 1017 Bac1188 RWWLWQPWR SEQ ID NO: 1018 Bac1189 WRGILYRSH SEQ ID NO: 1019 Bac1190 IGWQRNRKY SEQ ID NO: 1020 Bac1191 WIHKFRRKS SEQ ID NO: 1021 Bac1192 GKALHKNKI SEQ ID NO: 1022 Bac1193 KTKKKGVRK SEQ ID NO: 1023 Bac1194 WFIKWRLWA SEQ ID NO: 1024 Bac1195 GRKVYRVKV SEQ ID NO: 1025 Bac1196 NAKWHTWYR SEQ ID NO: 1026 Bac1197 TRGKIQISM SEQ ID NO: 1027 Bac1198 MTVIKRNLF SEQ ID NO: 1028 Bac1199 KRMALNQRH SEQ ID NO: 1029 Bac1200 RWVFNGSKV SEQ ID NO: 1030 Bac1201 RQGRLMGMA SEQ ID NO: 1031 Bac1202 IIYRRTPVG SEQ ID NO: 1032 Bac1203 LRRWKIMTT SEQ ID NO: 1033 Bac1204 YKKGNNWTA SEQ ID NO: 1034 Bac1205 TRWRWKRVS SEQ ID NO: 1035 Bac1206 RRAAPTGRG SEQ ID NO: 1036 Bac1207 YIKRWYGIW SEQ ID NO: 1037 Bac1208 PWGHIKKRK SEQ ID NO: 1038 Bac1209 TVGFPTQKR SEQ ID NO: 1039 Bac1210 KWVKGGWQV SEQ ID NO: 1040 Bacl2ll AFRIRKNID SEQ ID NO: 1041 Bac1212 VWRKKMVLV SEQ ID NO: 1042 Bac1213 FGYIKRGGP SEQ ID NO: 1043 Bac1214 KLRMVKWQG SEQ ID NO: 1044 Bac1215 KKWAAWQPR SEQ ID NO: 1045 Bac1216 RKSLKQKHW SEQ ID NO: 1046 Bac1217 HKRKQWQRG SEQ ID NO: 1047 Bac1218 RAKIPKRIM SEQ ID NO: 1048 Bac1219 VKQHHKNWR SEQ ID NO: 1049 Bac1220 RRWIPQKRR SEQ ID NO: 1050 Bac1221 AKRNFWKRW SEQ ID NO: 1051 Bac1222 LKWMWNVKR SEQ ID NO: 1052 Bac1223 KAGQWFGRM SEQ ID NO: 1053 Bac1224 VKWANIIWK SEQ ID NO: 1054 Bac1225 WWKKGLLAT SEQ ID NO: 1055 Bac1226 STLSYRRKF SEQ ID NO: 1056 Bac1227 RKSWWGVGR SEQ ID NO: 1057 Bac1228 RRIPRIQWV SEQ ID NO: 1058 Bac1229 WVARNRRWV SEQ ID NO: 1059 Bac1230 FGHPFLRKV SEQ ID NO: 1060 Bac1231 LLPQPRIFR SEQ ID NO: 1061 Bac1232 MVITRYRRW SEQ ID NO: 1062 Bac1233 GVKPKMLKL SEQ ID NO: 1063 Bac1234 LKTKHWLNW SEQ ID NO: 1064 Bac1235 FGHKFLMFR SEQ ID NO: 1065 Bac1236 RLVWRQWLR SEQ ID NO: 1066 Bac1237 QIRILKTRY SEQ ID NO: 1067 Bac1238 VRHTPKRVR SEQ ID NO: 1068 Bac1239 AGRSKRHPI SEQ ID NO: 1069 Bac1240 HSRILRKNK SEQ ID NO: 1070 Bac1241 KIQKYVANW SEQ ID NO: 1071 Bac1242 WAHGIKYFK SEQ ID NO: 1072 Bac1243 RSGHGRSYQ SEQ ID NO: 1073 Bac1244 IFMSWKSRW SEQ ID NO: 1074 Bac1245 HYSRKMAWR SEQ ID NO: 1075 Bac1246 KRWIVKWVK SEQ ID NO: 1076 Bac1247 WRNWPYKGK SEQ ID NO: 1077 Bac1248 RPYKPGWGK SEQ ID NO: 1078 Bac1249 WWAGPRLRI SEQ ID NO: 1079 Bac1250 TFQIKKPTW SEQ ID NO: 1080 Bac1251 GFAFKRTLR SEQ ID NO: 1081 Bac1252 QPNGRRYMA SEQ ID NO: 1082 Bac1253 HRNHWMNKW SEQ ID NO: 1083 Bac1254 NKRRVLIFI SEQ ID NO: 1084 Bac1255 WWAMKWIRV SEQ ID NO: 1085 Bac1256 GAKKFQWFQ SEQ ID NO: 1086 Bac1257 VAKTPTRNW SEQ ID NO: 1087 Bac1258 RMRHLRKVR SEQ ID NO: 1088 Bac1259 YGQRNMWRV SEQ ID NO: 1089 Bac1260 IMVMLKTVK SEQ ID NO: 1090 Bac1261 RLRRGISTK SEQ ID NO: 1091 Bac1262 HRVWVKWPY SEQ ID NO: 1092 Bac1263 MYIRGGNRF SEQ ID NO: 1093 Bac1264 RIRWTGYGI SEQ ID NO: 1094 Bac1265 PRRRTVRSM SEQ ID NO: 1095 Bac1266 RIYYMGFRT SEQ ID NO: 1096 Bac1267 YPPKFHKIK SEQ ID NO: 1097 Bac1268 YWRGWRHGL SEQ ID NO: 1098 Bac1269 RIKFFFNMW SEQ ID NO: 1099 Bac1270 IRVLIIMRR SEQ ID NO: 1100 Bac1271 HRRMVRLGV SEQ ID NO: 1101 Bac1272 FRRYIMNWW SEQ ID NO: 1102 Bac1273 HRHNRAPGS SEQ ID NO: 1103 Bac1274 GHKHFQKGQ SEQ ID NO: 1104 Bac1275 WNTPKFMLR SEQ ID NO: 1105 Bac1276 FMVWWKRPI SEQ ID NO: 1106 Bac1277 VKIKKRHQN SEQ ID NO: 1107 Bac1278 IVSTKRNNP SEQ ID NO: 1108 Bac1279 RMKTWKNWM SEQ ID NO: 1109 Bac1280 RRNWIRGIK SEQ ID NO: 1110 Bac1281 VWAKWWYAR SEQ ID NO: 1111 Bac1282 TSKKTKQVR SEQ ID NO: 1112 Bac1283 LIRALIFKW SEQ ID NO: 1113 Bac1284 SLWQTKVYK SEQ ID NO: 1114 Bac1285 NRVHRRVYW SEQ ID NO: 1115 Bac1286 HLRIRIYQL SEQ ID NO: 1116 Bac1287 PKKVRVNAH SEQ ID NO: 1117 Bac1288 NRWRYWFAA SEQ ID NO: 1118 Bac1289 WGQKRSRAF SEQ ID NO: 1119 Bac1290 RLWPTWRTW SEQ ID NO: 1120 Bac1291 IVGKKKMRM SEQ ID NO: 1121 Bac1292 PWKVVIVRW SEQ ID NO: 1122 Bac1293 WNFIGVIKR SEQ ID NO: 1123 Bac1294 RFVPRVTYT SEQ ID NO: 1124 Bac1295 RWGRHKRPQ SEQ ID NO: 1125 Bac1296 WRRVPRKWE SEQ ID NO: 1126 Bac1297 HGVRGFKHW SEQ ID NO: 1127 Bac1298 KNKRSQLVW SEQ ID NO: 1128 Bac1299 RIIPKYWWR SEQ ID NO: 1129 Bacl300 ILRLKFTYT SEQ ID NO: 1130 Bac1301 GVRPQIRRQ SEQ ID NO: 1131 Bac1302 QIHNRIRSF SEQ ID NO: 1132 Bac1303 RSAIRFGTG SEQ ID NO: 1133 Bac1304 RGRHNFVSI SEQ ID NO: 1134 Bac1305 AWRVMIYRF SEQ ID NO: 1135 Bac1306 KKNNGLWKH SEQ ID NO: 1136 Bac1307 RMQMRWKRK SEQ ID NO: 1137 Bac1308 VKTGRKWNN SEQ ID NO: 1138 Bac1309 PLFGSRRIK SEQ ID NO: 1139 Bac1310 RKWYIVQKK SEQ ID NO: 1140 Bacl3ll PIGFSRGMK SEQ ID NO: 1141 Bac1312 KAKVKTIWA SEQ ID NO: 1142 Bac1313 HKWRPVNRM SEQ ID NO: 1143 Bac1314 RHRVWVRRR SEQ ID NO: 1144 Bac1315 RPRTWAIRR SEQ ID NO: 1145 Bac1316 KFRYLKLAL SEQ ID NO: 1146 Bac1317 ASKMNPLYR SEQ ID NO: 1147 Bac1318 RLHVGRVKH SEQ ID NO: 1148 Bac1319 VVALQRRLW SEQ ID NO: 1149 Bac1320 LPRKWATGA SEQ ID NO: 1150 Bac1321 VWIHKVKGF SEQ ID NO: 1151 Bac1322 WVAWRWTRS SEQ ID NO: 1152 Bac1323 HNRKTFNGG SEQ ID NO: 1153 Bac1324 KGWLRANPR SEQ ID NO: 1154 Bac1325 SLNRKFHGK SEQ ID NO: 1155 Bac1326 IRGWWLKQG SEQ ID NO: 1156 Bac1327 KRRIRPRVR SEQ ID NO: 1157 Bac1328 FWPRYGTKF SEQ ID NO: 1158 Bac1329 IRTLRVFRT SEQ ID NO: 1159 Bac1330 WRNTWIRWN SEQ ID NO: 1160 Bac1331 RRRKYHTRD SEQ ID NO: 1161 Bac1332 ERPAFRMWR SEQ ID NO: 1162 Bac1333 LIVIRSKGR SEQ ID NO: 1163 Bac1334 WVTVYWKRF SEQ ID NO: 1164 Bac1335 FGSANYRQK SEQ ID NO: 1165 Bac1336 QTKYWQVAK SEQ ID NO: 1166 Bac1337 MVVMVVWRR SEQ ID NO: 1167 Bac1338 KWQTGKRTS SEQ ID NO: 1168 Bac1339 KWYRWRNHR SEQ ID NO: 1169 Bac1340 KTHWWRGRI SEQ ID NO: 1170 Bac1341 PSARRGWIY SEQ ID NO: 1171 Bac1342 KRAFKIRHI SEQ ID NO: 1172 Bac1343 GWYNPTRKI SEQ ID NO: 1173 Bac1344 VRNISFVRL SEQ ID NO: 1174 Bac1345 RRGTKKERS SEQ ID NO: 1175 Bac1346 ARRWKFIKT SEQ ID NO: 1176 Bac1347 GPGRAGVRN SEQ ID NO: 1177 Bac1348 PQIWGIKRK SEQ ID NO: 1178 Bac1349 KKVWHWFTG SEQ ID NO: 1179 Bac1350 RMRRRGKKW SEQ ID NO: 1180 Bac1351 RIERVNRKP SEQ ID NO: 1181 Bac1352 RTQYRYAHG SEQ ID NO: 1182 Bac1353 NKPRMPWYV SEQ ID NO: 1183 Bac1354 PHAYRVRFK SEQ ID NO: 1184 Bac1355 KNVRQAKIW SEQ ID NO: 1185 Bac1356 IWRGRVRAI SEQ ID NO: 1186 Bac1357 IWYLRIYKW SEQ ID NO: 1187 Bac1358 WRVRAGRWP SEQ ID NO: 1188 Bac1359 HMKRWHRWG SEQ ID NO: 1189 Bac1360 KGIYVWRRP SEQ ID NO: 1190 Bac1361 QKQIGTRTH SEQ ID NO: 1191 Bac1362 GMKVWRNLA SEQ ID NO: 1192 Bac1363 RIAMWKVFR SEQ ID NO: 1193 Bac1364 RKAGAIGAG SEQ ID NO: 1194 Bac1365 YSWRKKFQP SEQ ID NO: 1195 Bac1366 IRRIGGVGN SEQ ID NO: 1196 Bac1367 KRPWYNRKI SEQ ID NO: 1197 Bac1368 AHYNGYKRY SEQ ID NO: 1198 Bac1369 AWGRYTKVA SEQ ID NO: 1199 Bac1370 KRADAHRPI SEQ ID NO: 1200 Bac1371 ASRSKWNVI SEQ ID NO: 1201 Bac1372 RRGIPIKSR SEQ ID NO: 1202 Bac1373 MKLVNSRHL SEQ ID NO: 1203 Bac1374 HRIIiRVTVF SEQ ID NO: 1204 Bac1375 IRYIMNHGK SEQ ID NO: 1205 Bac1376 RKRRRQGFI SEQ ID NO: 1206 Bac1377 IKIRFAAQW SEQ ID NO: 1207 Bac1378 WGKMRMRVW SEQ ID NO: 1208 Bac1379 YRKINGGWY SEQ ID NO: 1209 Bac1380 WQAQKMWWR SEQ ID NO: 1210 Bac1381 RVHPFQKRL SEQ ID NO: 1211 Bac1382 TRIYGVWAR SEQ ID NO: 1212 Bac1383 RHRRKVKLI SEQ ID NO: 1213 Bac1384 KWRWVGIFM SEQ ID NO: 1214 Bac1385 WPKRFWNVW SEQ ID NO: 1215 Bac1386 NIIQKKMMG SEQ ID NO: 1216 Bac1387 KKWNRRRVK SEQ ID NO: 1217 Bac1388 WWKGGYIMK SEQ ID NO: 1218 Bac1389 NKIMAKRNW SEQ ID NO: 1219 Bac1390 KFSRGGIVIWW SEQ ID NO: 1220 Bac1391 GSHGWRRPP SEQ ID NO: 1221 Bac1392 LRNIKIPRS SEQ ID NO: 1222 Bac1393 KYFKARNSW SEQ ID NO: 1223 Bac1394 FWRMRQWKG SEQ ID NO: 1224 Bac1395 KLWDKRWMP SEQ ID NO: 1225 Bac1396 KSYWWTRWT SEQ ID NO: 1226 Bac1397 QRIRVVPYA SEQ ID NO: 1227 Bac1398 RQRVRGRKW SEQ ID NO: 1228 Bac1399 VPTRGRTQN SEQ ID NO: 1229 Bac1400 VRVRVSRWW SEQ ID NO: 1230 Bac1401 KQGNNRRYN SEQ ID NO: 1231 Bac1402 SYHRRARPK SEQ ID NO: 1232 Bac1403 WPYKHKRRI SEQ ID NO: 1233 Bac1404 WKKHLLKIM SEQ ID NO: 1234 Bac1405 ISGKRGSRR SEQ ID NO: 1235 Bac1406 KVGRKQWWI SEQ ID NO: 1236 Bac1407 RRAFRLQGK SEQ ID NO: 1237 Bac1408 GISKGIIRI SEQ ID NO: 1238 Bac1409 WWKNKHHWK SEQ ID NO: 1239 Bac1410 RVII3RWHRG SEQ ID NO: 1240 Bac1411 WRYWLVRNG SEQ ID NO: 1241 Bac1412 KRVWISIQI SEQ ID NO: 1242 Bac1413 GRWKVMNRT SEQ ID NO: 1243 Bac1414 IAWRVIVKW SEQ ID NO: 1244 Bac1415 NVWFVKRQQ SEQ ID NO: 1245 Bac1416 PRISRRRPW SEQ ID NO: 1246 Bac1417 TYWRRRPAV SEQ ID NO: 1247 Bac1418 IKRSHIITN SEQ ID NO: 1248 Bac1419 LKWWVGRAG SEQ ID NO: 1249 Bac1420 NSHGGRTRV SEQ ID NO: 1250 Bac1421 MRYAIWRTI SEQ ID NO: 1251 Bac1422 QIKRTWRRT SEQ ID NO: 1252 Bac1423 KMYIWKRKI SEQ ID NO: 1253 Bac1424 IFKMRTWTM SEQ ID NO: 1254 Bac1425 RAVWVRRMG SEQ ID NO: 1255 Bac1426 YWRQKINAW SEQ ID NO: 1256 Bac1427 GKYKWWRIR SEQ ID NO: 1257 Bac1428 MQRGFRKRK SEQ ID NO: 1258 Bac1429 WRRHWLPQN SEQ ID NO: 1259 Bac1430 WHIRRWKFI SEQ ID NO: 1260 Bac1431 WGSWRMRKH SEQ ID NO: 1261 Bac1432 KGWTNYNGR SEQ ID NO: 1262 Bac1433 VFIGKRTKS SEQ ID NO: 1263 Bac1434 GKPIGRKTY SEQ ID NO: 1264 Bac1435 RIRKWWSNH SEQ ID NO: 1265 Bac1436 RWIHTMWRG SEQ ID NO: 1266 Bac1437 WARKISNSW SEQ ID NO: 1267 Bac1438 WSRKRVWKF SEQ ID NO: 1268 Bac1439 WAWKLWIIK SEQ ID NO: 1269 Bac1440 GWAIGRGRI SEQ ID NO: 1270 Bac1441 YKIMTHPKKV SEQ ID NO: 1271 Bac1442 SGKGMRIHT SEQ ID NO: 1272 Bac1443 WKQHNVKLG SEQ ID NO: 1273 Bac1444 HYRVAYWPR SEQ ID NO: 1274 Bac1445 RMTMHISIK SEQ ID NO: 1275 Bac1446 KRMYKQAGI SEQ ID NO: 1276 Bac1447 WIKIHRGLS SEQ ID NO: 1277 Bac1448 PWIAHRRPR SEQ ID NO: 1278 Bac1449 QWKVIFRVW SEQ ID NO: 1279 Bac1450 RYIRRIVHG SEQ ID NO: 1280 Bac1451 MAYKFLIKN SEQ ID NO: 1281 Bac1452 PGSRYTRNW SEQ ID NO: 1282 Bac1453 QWKGTYIRP SEQ ID NO: 1283 Bac1454 KVWRKFQYF SEQ ID NO: 1284 Bac1455 IIFRKHRIL SEQ ID NO: 1285 Bac1456 WSGIWRRWF SEQ ID NO: 1286 Bac1457 RKWLKVTMR SEQ ID NO: 1287 Bac1458 VRQQWIIRW SEQ ID NO: 1288 Bac1459 YYQQGRLRY SEQ ID NO: 1289 Bac1460 LGTTFKRGT SEQ ID NO: 1290 Bac1461 AKRVTRGMS SEQ ID NO: 1291 Bac1462 VGRKGGWWL SEQ ID NO: 1292 Bac1463 YRMQVKWVR SEQ ID NO: 1293 Bac1464 RPGRWGRVW SEQ ID NO: 1294 Bac1465 IGGITVVKR SEQ ID NO: 1295 Bac1466 KSVMVVKGR SEQ ID NO: 1296 Bac1467 QYIRRAQMF SEQ ID NO: 1297 Bac1468 IKHWKWWAV SEQ ID NO: 1298 Bac1469 KHPFSKQSR SEQ ID NO: 1299 Bac1470 AISGKKRFW SEQ ID NO: 1300 Bac1471 RLRVRIWIL SEQ ID NO: 1301 Bac1472 KPQTRNWWV SEQ ID NO: 1302 Bac1473 WTKRWTQVN SEQ ID NO: 1303 Bac1474 RWRSVQILV SEQ ID NO: 1304 Bac1475 RHRWGWISK SEQ ID NO: 1305 Bac1476 GPGLGIVRR SEQ ID NO: 1306 Bac1477 GARHRILYW SEQ ID NO: 1307 Bac1478 VWLKGKHNN SEQ ID NO: 1308 Bac1479 YWVLRNMKN SEQ ID NO: 1309 Bac1480 YIVRRTLGV SEQ ID NO: 1310 Bac1481 RGKGIWMWN SEQ ID NO: 1311 Bac1482 IKNWPQIKT SEQ ID NO: 1312 Bac1483 NGAFKRTQK SEQ ID NO: 1313 Bac1484 KMWRWHGRW SEQ ID NO: 1314 Bac1485 KVWHINAIR SEQ ID NO: 1315 Bac1486 WWLQPKQWK SEQ ID NO: 1316 Bac1487 IKARGNRMS SEQ ID NO: 1317 Bac1488 KGTRMTAGW SEQ ID NO: 1318 Bac1489 GSHRIKVKW SEQ ID NO: 1319 Bac1490 TWRIDRIRR SEQ ID NO: 1320 Bac1491 AKVIIYWVKI SEQ ID NO: 1321 Bac1492 RTWIMITKV SEQ ID NO: 1322 Bac1493 GGKMPKIRG SEQ ID NO: 1323 Bac1494 KIGRKWVYG SEQ ID NO: 1324 Bac1495 KVKAMVGKM SEQ ID NO: 1325 Bac1496 SWRSVHSRK SEQ ID NO: 1326 Bac1497 VSRNSVVKK SEQ ID NO: 1327 Bac1498 ARWWGIRRR SEQ ID NO: 1328 Bac1499 SHRFRKHKR SEQ ID NO: 1329 Bac2000 ARWRIVVIRVRR SEQ ID NO: 1330 Bac2001 CRWRIVVIRVRR SEQ ID NO: 1331 Bac2002 DRWRIVVIRVRR SEQ ID NO: 1332 Bac2003 ERWRIVVIRVRR SEQ ID NO: 1333 Bac2004 FRWRIVVIRVRR SEQ ID NO: 1334 Bac2005 GRWRIVVIRVRR SEQ ID NO: 1335 Bac2006 HRWRIVVIRVRR SEQ ID NO: 1336 Bac2007 IRWRIVVIRVRR SEQ ID NO: 1337 Bac2008 KRWRIVVIRVRR SEQ ID NO: 1338 Bac2009 LRWRIVVIRVRR SEQ ID NO: 1339 Bac2010 MRWRIVVIRVRR SEQ ID NO: 1340 Bac2011 NRWRIVVIRVRR SEQ ID NO: 1341 Bac2012 PRWRIVVIRVRR SEQ ID NO: 1342 Bac2013 QRWRIVVIRVRR SEQ ID NO: 1343 Bac2014 SRWRIVVIRVRR SEQ ID NO: 1344 Bac2015 TRWRIVVIRVRR SEQ ID NO: 1345 Bac2016 VRWRIVVIRVRR SEQ ID NO: 1346 Bac2017 WRWRIVVIRVRR SEQ ID NO: 1347 Bac2018 YRWRIVVIRVRR SEQ ID NO: 1348 Bac2019 RAWRIVVIRVRR SEQ ID NO: 1349 Bac2020 RCWRIVVIRVRR SEQ ID NO: 1350 Bac2021 RDWRIVVIRVRR SEQ ID NO: 1351 Bac2022 REWRIVVIRVRR SEQ ID NO: 1352 Bac2023 RFWRIVVIRVRR SEQ ID NO: 1353 Bac2024 RGWRIVVIRVRR SEQ ID NO: 1354 Bac2025 RHWRIVVIRVRR SEQ ID NO: 1355 Bac2026 RIWRIVVIRVRR SEQ ID NO: 1356 Bac2027 RKWRIVVIRVRR SEQ ID NO: 1357 Bac2028 RLWRIVVIRVRR SEQ ID NO: 1358 Bac2029 RIVIWRIVVIRVRR SEQ ID NO: 1359 Bac2030 RNWRIVVIRVRR SEQ ID NO: 1360 Bac2031 RPWRIVVIRVRR SEQ ID NO: 1361 Bac2032 RQWRIVVIRVRR SEQ ID NO: 1362 Bac2033 RSWRIVVIRVRR SEQ ID NO: 1363 Bac2034 RTWRIVVIRVRR SEQ ID NO: 1364 Bac2035 RVWRIVVIRVRR SEQ ID NO: 1365 Bac2036 RWWRIVVIRVRR SEQ ID NO: 1366 Bac2037 RYWRIVVIRVRR SEQ ID NO: 1367 Bac2038 RRARIVVIRVRR SEQ ID NO: 1368 Bac2039 RRCRIVVIRVRR SEQ ID NO: 1369 Bac2040 RRDRIVVIRVRR SEQ ID NO: 1370 Bac2041 RRERIVVIRVRR SEQ ID NO: 1371 Bac2042 RRFRIVVIRVRR SEQ ID NO: 1372 Bac2043 RRGRIVVIRVRR SEQ ID NO: 1373 Bac2044 RRHRIVVIRVRR SEQ ID NO: 1374 Bac2045 RRIRIVVIRVRR SEQ ID NO: 1375 Bac2046 RRKRIVVIRVRR SEQ ID NO: 1376 Bac2047 RRLRIVVIRVRR SEQ ID NO: 1377 Bac2048 RRMRIVVIRVRR SEQ ID NO: 1378 Bac2049 RRNRIVVIRVRR SEQ ID NO: 1379 Bac2050 RRPRIVVIRVRR SEQ ID NO: 1380 Bac2051 RRQRIVVIRVRR SEQ ID NO: 1381 Bac2052 RRRRIVVIRVRR SEQ ID NO: 1382 Bac2053 RRSRIVVIRVRR SEQ ID NO: 1383 Bac2054 RRTRIVVIRVRR SEQ ID NO: 1384 Bac2055 RRVRIVVIRVRR SEQ ID NO: 1385 Bac2056 RRYRIVVIRVRR SEQ ID NO: 1386 Bac2057 RRWAIVVIRVRR SEQ ID NO: 1387 Bac2058 RRWCIVVIRVRR SEQ ID NO: 1388 Bac2059 RRWDIVVIRVRR SEQ ID NO: 1389 Bac2060 RRWEIVVIRVRR SEQ ID NO: 1390 Bac2061 RRWFIVVIRVRR, SEQ ID NO: 1391 Bac2062 RRWGIVVIRVRR SEQ ID NO: 1392 Bac2063 RRWHIVVIRVRR SEQ ID NO: 1393 Bac2064 RRWIIVVIRVRR SEQ ID NO: 1394 Bac2065 RRWKIVVIRVRR SEQ ID NO: 1395 Bac2066 RRWLIVVIRVRR SEQ ID NO: 1396 Bac2067 RRWMIVVIRVRR SEQ ID NO: 1397 Bac2068 RRWNIVVIRVRR SEQ ID NO: 1398 Bac2069 RRWPIVVIRVRR SEQ ID NO: 1399 Bac2070 RRWQIVVIRVRR SEQ ID NO: 1400 Bac2071 RRWSIVVIRVRR SEQ ID NO: 1401 Bac2072 RRWTIVVIRVRR SEQ ID NO: 1402 Bac2073 RRWVIVVIRVRR SEQ ID NO: 1403 Bac2074 RRWWIVVIRVRR SEQ ID NO: 1404 Bac2075 RRWYIVVIRVRR SEQ ID NO: 1405 Bac2076 RRWRAVVIRVRR SEQ ID NO: 1406 Bac2077 RRWRCVVIRVRR SEQ ID NO: 1407 Bac2078 RRWRDVVIRVRR SEQ ID NO: 1408 Bac2079 RRWREVVIRVRR SEQ ID NO: 1409 Bac2080 RRWRFVVIRVRR SEQ ID NO: 1410 Bac2081 RRWRGVVIRVRR SEQ ID NO: 1411 Bac2082 RRWRHVVIRVRR SEQ ID NO: 1412 Bac2083 RRWRKVVIRVRR SEQ ID NO: 1413 Bac2084 RRWRLVVIRVRR SEQ ID NO: 1414 Bac2085 RRWRMVVIRVRR SEQ ID NO: 1415 Bac2086 RRWRNVVIRVRR SEQ ID NO: 1416 Bac2087 RRWRPVVIRVRR SEQ ID NO: 1417 Bac2088 RRWRQVVIRVRR SEQ ID NO: 1418 Bac2089 RRWRRVVIRVRR SEQ ID NO: 1419 Bac2090 RRWRSVVIRVRR SEQ ID NO: 1420 Bac2091 RRWRTVVIRVRR SEQ ID NO: 1421 Bac2092 RRWRVVVIRVRR SEQ ID NO: 1422 Bac2093 RRWRWVVIRVRR SEQ ID NO: 1423 Bac2094 RRWRYVVIRVRR SEQ ID NO: 1424 Bac2095 RRWRIAVIRVRR SEQ ID NO: 1425 Bac2096 RRWRICVIRVRR SEQ ID NO: 1426 Bac2097 RRWRIDVIRVRR SEQ ID NO: 1427 Bac2098 RRWRIEVIRVRR SEQ ID NO: 1428 Bac2099 RRWRIFVIRVRR SEQ ID NO: 1429 Bac2100 RRWRIGVIRVRR SEQ ID NO: 1430 Bac2101 RRWRIHVIRVRR SEQ ID NO: 1431 Bac2102 RRWRIIVIRVRR SEQ ID NO: 1432 Bac2103 RRWRIKVIRVRR SEQ ID NO: 1433 Bac2104 RRWRILVIRVRR SEQ ID NO: 1434 Bac2105 RRWRIMVIRVRR SEQ ID NO: 1435 Bac2106 RRWRINVIRVRR SEQ ID NO: 1436 Bac2107 RRWRIPVIRVRR SEQ ID NO: 1437 Bac2108 RRWRIQVIRVRR SEQ ID NO: 1438 Bac2109 RRWRIRVIRVRR SEQ ID NO: 1439 Bac2110 RRWRISVIRVRR SEQ ID NO: 1440 Bac2lll RRWRITVIRVRR SEQ ID NO: 1441 Bac2112 RRWRIWVIRVRR SEQ ID NO: 1442 Bac2113 RRWRIYVIRVRR SEQ ID NO: 1443 Bac2114 RRWRIVAIRVRR SEQ ID NO: 1444 Bac2115 RRWRIVCIRVRR SEQ ID NO: 1445 Bac2116 RRWRIVDIRVRR SEQ ID NO: 1446 Bac2117 RRWRIVEIRVRR SEQ ID NO: 1447 Bac2118 RRWRIVFIRVRR SEQ ID NO: 1448 Bac2119 RRWRIVGIRVRR SEQ ID NO: 1449 Bac2120 RRWRIVHIRVRR SEQ ID NO: 1450 Bac2121 RRWRIVIIRVRR SEQ ID NO: 1451 Bac2122 RRWRIVKIRVRR SEQ ID NO: 1452 Bac2123 RRWRIVLIRVRR SEQ ID NO: 1453 Bac2124 RRWRIVMIRVRR SEQ ID NO: 1454 Bac2125 RRWRIVNIRVRR SEQ ID NO: 1455 Bac2126 RRWRIVPIRVRR SEQ ID NO: 1456 Bac2127 RRWRIVQIRVRR SEQ ID NO: 1457 Bac2128 RRWRIVRIRVRR SEQ ID NO: 1458 Bac2129 RRWRIVSIRVRR SEQ ID NO: 1459 Bac2130 RRWRIVTIRVRR SEQ ID NO: 1460 Bac2131 RRWRIVWIRVRR SEQ ID NO: 1461 Bac2132 RRWRIVYIRVRR SEQ ID NO:.1462 Bac2133 RRWRIVVARVRR SEQ ID NO: 1463 Bac2134 RRWRIVVCRVRR SEQ ID NO: 1464 Bac2135 RRWRIVVDRVRR SEQ ID NO: 1465 Bac2136 RRWRIVVERVRR SEQ ID NO: 1466 Bac2137 RRWRIVVFRVRR SEQ ID NO: 1467 Bac2138 RRWRIVVGRVRR SEQ ID NO: 1468 Bac2139 RRWRNVHRVRR SEQ ID NO: 1469 Bac2140 RRWRIVVKRVRR SEQ ID NO: 1470 Bac2141 RRWRIVVLRVRR SEQ ID NO: 1471 Bac2142 RRWRIVVMRVRR SEQ ID NO: 1472 Bac2143 RRWRIVVNRVRR SEQ ID NO: 1473 Bac2144 RRWRIVVPRVRR SEQ ID NO: 1474 Bac2145 RRWRIVVQRVRR SEQ ID NO: 1475 Bac2146 RRWRIVVRRVRR SEQ ID NO: 1476 Bac2147 RRWRIVVSRVRR SEQ ID NO: 1477 Bac2148 RRWRIVVTRVRR SEQ ID NO: 1478 Bac2149 RRWRIVVVRVRR SEQ ID NO: 1479 Bac2150 RRWRIVVWRVRR SEQ ID NO: 1480 Bac2151 RRWRIVVYRVRR SEQ ID NO: 1481 Bac2152 RRWRIVVIAVRR SEQ ID NO: 1482 Bac2153 RRWRIVVICVRR SEQ ID NO: 1483 Bac2154 RRWRIVVIDVRR SEQ ID NO: 1484 Bac2155 RRWRIVVIEVRR SEQ ID NO: 1485 Bac2156 RRWRIVVIFVRR SEQ ID NO: 1486 Bac2157 RRWRIVVIGVRR SEQ ID NO: 1487 Bac2158 RRWRIVVIHVRR SEQ ID NO: 1488 Bac2159 RRWRIVVIIVRR SEQ ID NO: 1489 Bac2160 RRWRIVVIKVRR SEQ ID NO: 1490 Bac2161 RRWRIVVILVRR SEQ ID NO: 1491 Bac2162 RRWRIVVIMVRR SEQ ID NO: 1492 Bac2163 RRWRIVVINVRR SEQ ID NO: 1493 Bac2164 RRWRIVVIPVRR SEQ ID NO: 1494 Bac2165 RRWRIVVIQVRR SEQ ID NO: 1495 Bac2166 RRWRIVVISVRR SEQ ID NO: 1496 Bac2167 RRWRIVVITVRR SEQ ID NO: 1497 Bac2168 RRWRIVVIVVRR SEQ ID NO: 1498 Bac2169 RRWRIVVIWVRR SEQ ID NO: 1499 Bac2170 RRWRIVVIYVRR SEQ ID NO: 1500 Bac2171 RRWRIVVIRARR SEQ ID NO: 1501 Bac2172 RRWRIVVIRCRR SEQ ID NO: 1502 Bac2173 RRWRIVVIRDRR SEQ ID NO: 1503 Bac2174 RRWRIVVIRERR SEQ ID NO: 1504 Bac2175 RRWRIVVIRFRR SEQ ID NO: 1505 Bac2176 RRWRIVVIRGRR SEQ ID NO: 1506 Bac2177 RRWRIVVIRHRR SEQ ID NO: 1507 Bac2178 RRWRIVVIRIRR SEQ ID NO: 1508 Bac2179 RRWRIVVIRKRR SEQ ID NO: 1509 Bac2180 RRWRIVVIRLRR SEQ ID NO: 1510 Bac2181 RRWRIVVIRMRR SEQ ID NO: 1511 Bac2182 RRWRIVVIRNRR SEQ ID NO: 1512 Bac2183 RRWRIVVIRPRR SEQ ID NO: 1513 Bac2184 RRWRIVVIRQRR SEQ ID NO: 1514 Bac2185 RRWRIVVIRRRR SEQ ID NO: 1515 Bac2186 RRWRIVVIRSRR SEQ ID NO: 1516 Bac2187 RRWRIVVIRTRR SEQ ID NO: 1517 Bac2188 RRWRIVVIRWRR SEQ ID NO: 1518 Bac2189 RRWRIVVIRYRR SEQ ID NO: 1519 Bac2190 RRWRIVVIRVAR SEQ ID NO: 1520 Bac2191 RRWRIVVIRVCR SEQ ID NO: 1521 Bac2192 RRWRIVVIRVDR SEQ ID NO: 1522 Bac2193 RRWRIVVIRVER SEQ ID NO: 1523 Bac2194 RRWRIVVIRVFR SEQ ID NO: 1524 Bac2195 RRWRIVVIRVGR SEQ ID NO: 1525 Bac2196 RRWRIVVIRVHR SEQ ID NO: 1526 Bac2197 RRWRIVVIRVIR SEQ ID NO: 1527 Bac2198 RRWRIVVIRVKR SEQ ID NO: 1528 Bac2199 RRWRIVVIRVLR SEQ ID NO: 1529 Bac2200 RRWRIVVIRVMR SEQ ID NO: 1530 Bac2201 RRWRIVVIRVNR SEQ ID NO: 1531 Bac2202 RRWRIVVIRVPR SEQ ID NO: 1532 Bac2203 RRWRIVVIRVQR SEQ ID NO: 1533 Bac2204 RRWRIVVIRVSR SEQ ID NO: 1534 Bac2205 RRWRIVVIRVTR SEQ ID NO: 1535 Bac2206 RRWRIVVIRVVR SEQ ID NO: 1536 Bac2207 RRWRIVVIRVWR SEQ ID NO: 1537 Bac2208 RRWRIVVIRVYR SEQ ID NO: 1538 Bac2209 RRWRIVVIRVRA SEQ ID NO: 1539 Bac2210 RRWRIVVIRVRC SEQ ID NO: 1540 Bac2211 RRWRWVIRVRD SEQ ID NO: 1541 Bac2212 RRWRIVVIRVRE SEQ ID NO: 1542 Bac2213 RRWRIVVIRVRF SEQ ID NO: 1543 Bac2214 RRWRIVVIRVRG SEQ ID NO: 1544 Bac2215 RRWRIVVIRVRH SEQ ID NO: 1545 Bac2216 RRWRIVVIRVRI SEQ ID NO: 1546 Bac2217 RRWRIVVIRVRK SEQ ID NO: 1547 Bac2218 RRWRIVVIRVRL SEQ ID NO: 1548 Bac2219 RRWRIVVIRVRM SEQ ID NO: 1549 Bac2220 RRWRIVVIRVRN SEQ ID NO: 1550 Bac2221 RRWRIVVIRVRP SEQ ID NO: 1551 Bac2222 RRWRIVVIRVRQ SEQ ID NO: 1552 Bac2223 RRWRIVVIRVRS SEQ ID NO: 1553 Bac2224 RRWRIVVIRVRT SEQ ID NO: 1554 Bac2225 RRWRIVVIRVRV SEQ ID NO: 1555 Bac2226 RRWRIVVIRVRW SEQ ID NO: 1556 Bac2227 RRWRIVVIRVRY SEQ ID NO: 1557 Bac2228 AWWKIWVIRWWR SEQ ID NO: 1558 Bac2229 CWWKIWVIRWWR SEQ ID NO: 1559 Bac2230 DWWKIWVIRWWR SEQ ID NO: 1560 Bac2231 EWWKIWVIRWWR SEQ ID NO: 1561 Bac2232 FWWKIVWIRWWR SEQ ID NO: 1562 Bac2233 GWWKIWVIRWWR SEQ ID NO: 1563 Bac2234 HWWKIWVIRWWR SEQ ID NO: 1564 Bac2235 IWWKIWVIRWWR SEQ ID NO: 1565 Bac2236 KWWKIWVIRWWR SEQ ID NO: 1566 Bac2237 LWWKIWVIRWWR SEQ ID NO: 1567 Bac2238 MWWKIWVIRWWR SEQ ID NO: 1568 Bac2239 NWWKIWVIRWWR SEQ ID NO: 1569 Bac2240 PWWKIWVIRWWR SEQ ID NO: 1570 Bac2241 QWWKIWVIRWWR SEQ ID NO: 1571 Bac2242 SWWKIWVIRWWR SEQ ID NO: 1572 Bac2243 TWWKIWVIRWWR SEQ ID NO: 1573 Bac2244 VWWKIWVIRWWR SEQ ID NO: 1574 Bac2245 WWWKIWVIRWWR SEQ ID NO: 1575 Bac2246 YWWKIWVIRWWR SEQ ID NO: 1576 Bac2247 RAWKIWVIRWWR SEQ ID NO: 1577 Bac2248 RCWKIWVIRWWR SEQ ID NO: 1578 Bac2249 RDWKIWVIRWWR SEQ ID NO: 1579 Bac2250 REWKIWVIRWWR SEQ ID NO: 1580 Bac2251 RFWKIWVIRWWR SEQ ID NO: 1581 Bac2252 RGWKIWVIRWWR SEQ ID NO: 1582 Bac2253 RHWKIWVIRWWR SEQ ID NO: 1583 Bac2254 RIWKIWVIRWWR SEQ ID NO: 1584 Bac2255 RKWKIWVIRWWR SEQ ID NO: 1585 Bac2256 RLWKIWVIRWWR SEQ ID NO: 1586 Bac2257 RMWKIWVIRWWR SEQ ID NO: 1587 Bac2258 RNWKIWVIRWWR SEQ ID NO: 1588 Bac2259 RPWKIWVIRWWR SEQ ID NO: 1589 Bac2260 RQWKIWVIRWWR SEQ ID NO: 1590 Bac2261 RRWKIWVIRWWR SEQ ID NO: 1591 Bac2262 RSWKIWVIRWWR SEQ ID NO: 1592 Bac2263 RTWKIWVIRWWR SEQ ID NO: 1593 Bac2264 RVWKIWVIRWWR SEQ ID NO: 1594 Bac2265 RYWKIWVIRWVWR SEQ ID NO: 1595 Bac2266 RWAKIWVIRWWR SEQ ID NO: 1596 Bac2267 RWCKIVWIRWWR SEQ ID NO: 1597 Bac2268 RWDKIWVIRWVWR SEQ ID NO: 1598 Bac2269 RWEKIVWIRWWR SEQ ID NO: 1599 Bac2270 RWFKIWVIRWWR SEQ ID NO: 1600 Bac2271 RWGKIWVIRWVWR SEQ ID NO: 1601 Bac2272 RWHKIWVIRWWR SEQ ID NO: 1602 Bac2273 RWIKIWVIRWWR SEQ ID NO: 1603 Bac2274 RWKKIWVIRWWR SEQ ID NO: 1604 Bac2275 RWLKIVWIRWWR SEQ ID NO: 1605 Bac2276 RWMKIWVIRWWR SEQ ID NO: 1606 Bac2277 RWNKIWVIRWWR SEQ ID NO: 1607 Bac2278 RWPKIVWIRWWR SEQ ID NO: 1608 Bac2279 RWQKIWVIRWWR SEQ ID NO: 1609 Bac2280 RWRKIWVIRWWR SEQ ID NO: 1610 Bac2281 RWSKIWVIRVVWR SEQ ID NO: 1611 Bac2282 RWTKIWVIRWWR SEQ ID NO: 1612 Bac2283 RWVKIWVIRWWR SEQ ID NO: 1613 Bac2284 RWYKIWVIRWWR SEQ ID NO: 1614 Bac2285 RWWAIWVIRWVWR SEQ ID NO: 1615 Bac2286 RWWCIWVIRWWR SEQ ID NO: 1616 Bac2287 RWWDIWVIRWWR SEQ ID NO: 1617 Bac2288 RWWEIWVIRWWR SEQ ID NO: 1618 Bac2289 RWWFIWVIRVWWR SEQ ID NO: 1619 Bac2290 RWWGIWVIRWWR SEQ ID NO: 1620 Bac2291 RWWHIWVIRWWR SEQ ID NO: 1621 Bac2292 RWWIIWVIRWWR SEQ ID NO: 1622 Bac2293 RWWLIWVIRWWR SEQ ID NO: 1623 Bac2294 RWWMIWVIRWWR SEQ ID NO: 1624 Bac2295 RWWNIWVIRWWR SEQ ID NO: 1625 Bac2296 RWWPIWVIRWWR SEQ ID NO: 1626 Bac2297 RWWQIWVIRWWR SEQ ID NO: 1627 Bac2298 RWWRIWVII2WWR SEQ ID NO: 1628 Bac2299 RWWSIWVIRWWR SEQ ID NO: 1629 Bac2300 RWWTIWVIRWWR SEQ ID NO: 1630 Bac2301 RWWVIWVIRWWR SEQ ID NO: 1631 Bac2302 RWWWIWVIRWWR SEQ ID NO: 1632 Bac2303 RWWYIWVIRWWR SEQ ID NO: 1633 Bac2304 RWWKAWVIRWWR SEQ ID NO: 1634 Bac2305 RWWKCWVIRWWR SEQ ID NO: 1635 Bac2306 RWWKDWVIRWWR SEQ ID NO: 1636 Bac2307 RWWKEWVIRWWR SEQ ID NO: 1637 Bac2308 RWWKFWVIRWWR SEQ ID NO: 1638 Bac2309 RWWKGWVIRWWR SEQ ID NO: 1639 Bac2310 RWWKHWVIRWVWR SEQ ID NO: 1640 Bac2311 RWWKKWVIRWWR SEQ ID NO: 1641 Bac2312 RWWKLWVIRWWR SEQ ID NO: 1642 Bac2313 RWWKMWVIRWWR SEQ ID NO: 1643 Bac2314 RWWKNWVIRWWR SEQ ID NO: 1644 Bac2315 RWWKPWVIRWWR SEQ ID NO: 1645 Bac2316 RWWKQWVIRWWR SEQ ID NO: 1646 Bac2317 RWWKRWVIRWWR SEQ ID NO: 1647 Bac2318 RWWKSWVIRWWR SEQ ID NO: 1648 Bac2319 RWWKTWVIRWWR SEQ ID NO: 1649 Bac2320 RWWKVWVIRWWR SEQ ID NO: 1650 Bac2321 RWWKWWVIRWWR SEQ ID NO: 1651 Bac2322 RWWKYWVIRWWR SEQ ID NO: 1652 Bac2323 RWWKIAVIRWWR SEQ ID NO: 1653 Bac2324 RWWKICVIRWWR SEQ ID NO: 1654 Bac2325 RWWKIDVIRWWR SEQ ID NO: 1655 Bac2326 RWWKIEVIRWWR SEQ ID NO: 1656 Bac2327 RWWKIFVIRWWR SEQ ID NO: 1657 Bac2328 RWWKIGVIRWWR SEQ ID NO: 1658 Bac2329 RWWKIHVIRWWR SEQ ID NO: 1659 Bac2330 RWWKIIVIRWWR SEQ ID NO: 1660 Bac2331 RWWKIKVIRWWR SEQ ID NO: 1661 Bac2332 RWWKILVIRWWR SEQ ID NO: 1662 Bac2333 RWWKIMVIRWWR SEQ ID NO: 1663 Bac2334 RWWKINVIRWWR SEQ ID NO: 1664 Bac2335 RWWKIPVIRWWR SEQ ID NO: 1665 Bac2336 RWWKIQVIRWWR SEQ ID NO: 1666 Bac2337 RWWKIRVIRWWR SEQ ID NO: 1667 Bac2338 RWWKISVIRWWR SEQ ID NO: 1668 Bac2339 RWWKITVIRWWR SEQ ID NO: 1669 Bac2340 RWWKIVVIRWWR SEQ ID NO: 1670 Bac2341 RWWKIYVIRWWR SEQ ID NO: 1671 Bac2342 RWWKIWAIRWWR SEQ ID NO: 1672 Bac2343 RWWKIWCIRWWR SEQ ID NO: 1673 Bac2344 RWWKIWDIRWWR SEQ ID NO: 1674 Bac2345 RWWKIWEIRWWR SEQ ID NO: 1675 Bac2346 RWWKIWFIRWWR SEQ ID NO: 1676 Bac2347 RWWKIWGIRWWR SEQ ID NO: 1677 Bac2348 RWWKIWHIRWWR SEQ ID NO: 1678 Bac2349 RWWKIWIIRWWR SEQ ID NO: 1679 Bac2350 RWWKIWKIRWWR SEQ ID NO: 1680 Bac2351 RWWKIWLIRWWR SEQ ID NO: 1681 Bac2352 RWWKIWMIRWWR SEQ ID NO: 1682 Bac2353 RWWKIWNIRWWR SEQ ID NO: 1683 Bac2354 RWWKIWPIRWWR SEQ ID NO: 1684 Bac2355 RWWKIWQIRWWR SEQ ID NO: 1685 Bac2356 RWWKIWRIRWWR SEQ ID NO: 1686 Bac2357 RWWKIWSIRWWR SEQ ID NO: 1687 Bac2358 RWWKIWTIRWWR SEQ ID NO: 1688 Bac2359 RWWKIWWIRWWR SEQ ID NO: 1689 Bac2360 RWWKIWYIRWWR SEQ ID NO: 1690 Bac2361 RWWKIWVARWWR SEQ ID NO: 1691 Bac2362 RWWKIWVCRWWR SEQ ID NO: 1692 Bac2363 RWWKIWVDRWWR SEQ ID NO: 1693 Bac2364 RWWKIWVERWWR SEQ ID NO: 1694 Bac2365 RWWKIWVFRWWR SEQ ID NO: 1695 Bac2366 RWWKIWVGRWWR SEQ ID NO: 1696 Bac2367 RWWKIWVHRWWR SEQ ID NO: 1697 Bac2368 RWWKIWVKRWWR SEQ ID NO: 1698 Bac2369 RWWKIWVLRWWR SEQ ID NO: 1699 Bac2370 RWWKIWVMRWWR SEQ ID NO: 1700 Bac2371 RWWKIWVNRWWR SEQ ID NO: 1701 Bac2372 RWWKIWVPRWWR SEQ ID NO: 1702 Bac2373 RWWKIWVQRWWR SEQ ID NO: 1703 Bac2374 RWWKIWVRRWWR SEQ ID NO: 1704 Bac2375 RWWKIWVSRWWR SEQ ID NO: 1705 Bac2376 RWWKIWVTRWWR SEQ ID NO: 1706 Bac2377 RWWKIWVVRWWR SEQ ID NO: 1707 Bac2378 RWWKIWVWRWWR SEQ ID NO: 1708 Bac2379 RWWKIWVYRWWR SEQ ID NO: 1709 Bac2380 RWWKIWVIAWWR SEQ ID NO: 1710 Bac2381 RWWKIWVICWWR SEQ ID NO: 1711 Bac2382 RWWKIWVIDWWR SEQ ID NO: 1712 Bac2383 RWWKIWVIEWWR SEQ ID NO: 1713 Bac2384 RWWKIWVIFWWR SEQ ID NO: 1714 Bac2385 RWWKIWVIGWWR SEQ ID NO: 1715 Bac2386 RWWKIWVIHWWR SEQ ID NO: 1716 Bac2387 RWWKIWVIIWWR SEQ ID NO: 1717 Bac2388 RWWKIWVIKWWR SEQ ID NO: 1718 Bac2389 RWWKIWVILWWR SEQ ID NO: 1719 Bac2390 RWWKIWVIMWWR SEQ ID NO: 1720 Bac2391 RWWKIWVINWWR SEQ ID NO: 1721 Bac2392 RWWKIWVIPWWR SEQ ID NO: 1722 Bac2393 RWWKIWVIQWWR SEQ ID NO: 1723 Bac2394 RWWKIWVISWWR SEQ ID NO: 1724 Bac2395 RWWKIWVITWWR SEQ ID NO: 1725 Bac2396 RWWKIWVIVWWR SEQ ID NO: 1726 Bac2397 RWWKIWVIWWWR SEQ ID NO: 1727 Bac2398 RWWKIWVIYWWR SEQ ID NO: 1728 Bac2399 RWWKIWVIRAWR SEQ ID NO: 1729 Bac2400 RWWKIWVIRCWR SEQ ID NO: 1730 Bac2401 RWWKIWVIRDWR SEQ ID NO: 1731 Bac2402 RWWKIWVIREWR SEQ ID NO: 1732 Bac2403 RWWKIWVIRFWR SEQ ID NO: 1733 Bac2404 RWWKIWVIRGWR SEQ ID NO: 1734 Bac2405 RWWKIWVIRHWR SEQ ID NO: 1735 Bac2406 RWWKIWVIRIWR SEQ ID NO: 1736 Bac2407 RWWKIWVIRKWR SEQ ID NO: 1737 Bac2408 RWWKIWVIRLWR SEQ ID NO: 1738 Bac2409 RWWKIWVIRMWR SEQ ID NO: 1739 Bac2410 RWWKIWVIRNWR SEQ ID NO: 1740 Bac2411 RWWKIWVIRPWR SEQ ID NO: 1741 Bac2412 RWWKIWVIRQWR SEQ ID NO: 1742 Bac2413 RWWKIWVII2RWR SEQ ID NO: 1743 Bac2414 RWWKIWVIRSWR SEQ ID NO: 1744 Bac2415 RWWKIWVIRTWR SEQ ID NO: 1745 Bac2416 RWWKIWVIRVWR SEQ ID NO: 1746 Bac2417 RWWKIWVIRYWR SEQ ID NO: 1747 Bac2418 RWWKIWVIRWAR SEQ ID NO: 1748 Bac2419 RWWKIWVIRWCR SEQ ID NO: 1749 Bac2420 RWWKIWVIRWDR SEQ ID NO: 1750 Bac2421 RWWKIWVIRWER SEQ ID NO: 1751 Bac2422 RWVWKIWVIRWFR SEQ ID NO: 1752 Bac2423 RWWKIWVIRWGR SEQ ID NO: 1753 Bac2424 RWWKIWVIRWHR SEQ ID NO: 1754 Bac2425 RWWKIWVIRWIR SEQ ID NO: 1755 Bac2426 RWWKIWVIRWKR SEQ ID NO: 1756 Bac2427 RWWKIWVIRWLR SEQ ID NO: 1757 Bac2428 RWWKIWVIRWMR SEQ ID NO: 1758 Bac2429 RWWKIWVIRWNR SEQ ID NO: 1759 Bac2430 RWWKIWVIRWPR SEQ ID NO: 1760 Bac2431 RWWKIWVIRWQR SEQ ID NO: 1761 Bac2432 RWWKIWVIRWRR SEQ ID NO: 1762 Bac2433 RWWKIWVIRWSR SEQ ID NO: 1763 Bac2434 RWWKIWVIRWTR SEQ ID NO: 1764 Bac2435 RWWKIWVIRWVR SEQ ID NO: 1765 Bac2436 RWWKIWVIRWYR SEQ ID NO: 1766 Bac2437 RWWKIWVIRWWA SEQ ID NO: 1767 Bac2438 RWWKIWVIRWWC SEQ ID NO: 1768 Bac2439 RWWKIWVIRWWD SEQ ID NO: 1769 Bac2440 RWWKIWVIRWWE SEQ ID NO: 1770 Bac2441 RWWKIWVIRWWF SEQ ID NO: 1771 Bac2442 RWWKIWVIRWWG SEQ ID NO: 1772 Bac2443 RWWKIWVIRWWH SEQ ID NO: 1773 Bac2444 RWWKIWVIRWWI SEQ ID NO: 1774 Bac2445 RWWKIWVIRWWK SEQ ID NO: 1775 Bac2446 RWWKIWVIRWWL SEQ ID NO: 1776 Bac2447 RWWKIWVIRWWM SEQ ID NO: 1777 Bac2448 RWWKIWVIRWWN SEQ ID NO: 1778 Bac2449 RWWKIWVIRWWP SEQ ID NO: 1779 Bac2450 RWWKIWVIRWWQ SEQ ID NO: 1780 Bac2451 RWWKIWVIRWWS SEQ ID NO: 1781 Bac2452 RWWKIWVIRWWT SEQ ID NO: 1782 Bac2453 RWWKIWVIRWWV SEQ ID NO: 1783 Bac2454 RWWKTWVIRWWW SEQ ID NO: 1784 Bac2455 RWWKIWVIRWWY SEQ ID NO: 1785 Bac2456 ARAAVVLIVIRR SEQ ID NO: 1786 Bac2457 CRAAVVLIVIRR SEQ ID NO: 1787 Bac2458 DRAAVVLIVIRR SEQ ID NO: 1788 Bac2459 ERAAVVLIVIRR SEQ ID NO: 1789 Bac2460 FRAAVVLIVIRR SEQ ID NO: 1790 Bac2461 GRAAVVLIVIRR SEQ ID NO: 1791 Bac2462 HRAAVVLIVIRR SEQ ID NO: 1792 Bac2463 IRAAVVLIVIRR SEQ ID NO: 1793 Bac2464 KRAAVVLIVIRR SEQ ID NO: 1794 Bac2465 LRAAVVLIVIRR SEQ ID NO: 1795 Bac2466 MRAAVVLIVIRR SEQ ID NO: 1796 Bac2467 NRAAVVLIVIRR SEQ ID NO: 1797 Bac2468 PRAAVVLIVIRR SEQ ID NO: 1798 Bac2469 QRAAVVLIVIRR SEQ ID NO: 1799 Bac2470 SRAAVVLIVIRR SEQ ID NO: 1800 Bac2471 TRAAVVLIVIRR SEQ ID NO: 1801 Bac2472 VRAAVVLIVIRR SEQ ID NO: 1802 Bac2473 WRAAVVLIVIRR SEQ ID NO: 1803 Bac2474 YRAAVVLIVIRR SEQ ID NO: 1804 Bac2475 RAAAVVLIVIRR SEQ ID NO: 1805 Bac2476 RCAAVVLIVIRR SEQ ID NO: 1806 Bac2477 RDAAVVLIVIRR SEQ ID NO: 1807 Bac2478 REAAVVLIVIRR SEQ ID NO: 1808 Bac2479 RFAAVVLIVIRR SEQ ID NO: 1809 Bac2480 RGAAVVLIVIRR SEQ ID NO: 1810 Bac2481 RHAAVVLIVIRR SEQ ID NO: 1811 Bac2482 RIAAVVLIVIRR SEQ ID NO: 1812 Bac2483 RKAAVVLIVIRR SEQ ID NO: 1813 Bac2484 RLAAVVLIVIRR SEQ ID NO: 1814 Bac2485 RMAAVVLIVIRR SEQ ID NO: 1815 Bac2486 RNAAVVLIVIRR SEQ ID NO: 1816 Bac2487 RPAAVVLIVIRR SEQ ID NO: 1817 Bac2488 RQAAVVLIVIRR SEQ ID NO: 1818 Bac2489 RSAAVVLIVIRR SEQ ID NO: 1819 Bac2490 RTAAVVLIVIRR SEQ ID NO: 1820 Bac2491 RVAAVVLIVIRR SEQ ID NO: 1821 Bac2492 RWAAVVLIVIRR SEQ ID NO: 1822 Bac2493 RYAAVVLIVIRR SEQ ID NO: 1823 Bac2494 RRCAVVLIVIRR SEQ ID NO: 1824 Bac2495 RRDAVVLIVIRR SEQ ID NO: 1825 Bac2496 RREAVVLIVIRR SEQ ID NO: 1826 Bac2497 RRFAVVLIVIRR SEQ ID NO: 1827 Bac2498 RRGAVVLIVIRR SEQ ID NO: 1828 Bac2499 RRHAVVLIVIRR SEQ ID NO: 1829 Bac2500 RRIAVVLIVIRR SEQ ID NO: 1830 Bac2501 RRKAVVLIVIRR SEQ ID NO: 1831 Bac2502 RRLAVVLIVIRR SEQ ID NO: 1832 Bac2503 RRMAVVLIVIRR SEQ ID NO: 1833 Bac2504 RRNAVVLIVIRR SEQ ID NO: 1834 Bac2505 RRPAVVLIVIRR SEQ ID NO: 1835 Bac2506 RRQAVVLIVIRR SEQ ID NO: 1836 Bac2507 RRRAVVLIVIRR SEQ ID NO: 1837 Bac2508 RRSAVVLIVIRR SEQ ID NO: 1838 Bac2509 RRTAVVLIVIRR SEQ ID NO: 1839 Bac2510 RRVAVVLIVIRR SEQ ID NO: 1840 Bac2511 RRWAVVLIVIRR SEQ ID NO: 1841 Bac2512 RRYAVVLIVIRR SEQ ID NO: 1842 Bac2513 RRACVVLIVIRR SEQ ID NO: 1843 Bac2514 RRADVVLIVIRR SEQ ID NO: 1844 Bac2515 RRAEVVLIVIRR SEQ ID NO: 1845 Bac2516 RRAFVVLIVIRR SEQ ID NO: 1846 Bac2517 RRAGVVLIVIRR SEQ ID NO: 1847 Bac2518 RRAHVVLIVIRR SEQ ID NO: 1848 Bac2519 RRAIVVLIVIRR SEQ ID NO: 1849 Bac2520 RRAKVVLIVIRR SEQ ID NO: 1850 Bac2521 RRALVVLIVIRR SEQ ID NO: 1851 Bac2522 RRAMVVLIVIRR SEQ ID NO: 1852 Bac2523 RRANVVLIVIRR SEQ ID NO: 1853 Bac2524 RRAPVVLIVIRR SEQ ID NO: 1854 Bac2525 RRAQVVLIVIRR SEQ ID NO: 1855 Bac2526 RRARVVLIVIRR SEQ ID NO: 1856 Bac2527 RRASVVLIVIRR SEQ ID NO: 1857 Bac2528 RRATVVLIVIRR SEQ ID NO: 1858 Bac2529 RRAVVVLIVIRR SEQ ID NO: 1859 Bac2530 RRAWVVLIVIRR SEQ ID NO: 1860 Bac2531 RRAYVVLIVIRR SEQ ID NO: 1861 Bac2532 RRAAAVLIVIRR SEQ ID NO: 1862 Bac2533 RRAACVLIVIRR SEQ ID NO: 1863 Bac2534 RRAADVLIVIRR SEQ ID NO: 1864 Bac2535 RRAAEVLIVIRR SEQ ID NO: 1865 Bac2536 RRAAFVLIVIRR SEQ ID NO: 1866 Bac2537 RRAAGVLIVIRR SEQ ID NO: 1867 Bac2538 RRAAHVLIVIRR SEQ ID NO: 1868 Bac2539 RRAAIVLIVIRR SEQ ID NO: 1869 Bac2540 RRAAKVLIVIRR SEQ ID NO: 1870 Bac2541 RRAALVLIVIRR SEQ ID NO: 1871 Bac2542 RRAAMVLIVIRR SEQ ID NO: 1872 Bac2543 RRAANVLIVIRR SEQ ID NO: 1873 Bac2544 RRAAPVLIVIRR SEQ ID NO: 1874 Bac2545 RRAAQVLIVIRR SEQ ID NO: 1875 Bac2546 RRAARVLIVIl2R SEQ ID NO: 1876 Bac2547 RRAASVLIVIRR SEQ ID NO: 1877 Bac2548 RRAATVLIVIRR SEQ ID NO: 1878 Bac2549 RRAAWVLIVIRR SEQ ID NO: 1879 Bac2550 RRAAYVLIVIRR SEQ ID NO: 1880 Bac2551 RRAAVALIVIRR SEQ ID NO: 1881 Bac2552 RRAAVCLIVIRR SEQ ID NO: 1882 Bac2553 RRAAVDLIVIRR SEQ ID NO: 1883 Bac2554 RRAAVELIVIRR SEQ ID NO: 1884 Bac2555 RRAAVFLIVIRR SEQ ID NO: 1885 Bac2556 RRAAVGLIVIRR SEQ ID NO: 1886 Bac2557 RRAAVHLIVIRR SEQ ID NO: 1887 Bac2558 RRAAVILIVIRR SEQ ID NO: 1888 Bac2559 RRAAVKLIVIRR SEQ ID NO: 1889 Bac2560 RRAAVLLIVIRR SEQ ID NO: 1890 Bac2561 RRAAVMLIVIRR SEQ ID NO: 1891 Bac2562 RRAAVNLIVIRR SEQ ID NO: 1892 Bac2563 RRAAVPLIVIRR SEQ ID NO: 1893 Bac2564 RRAAVQLIVIRR SEQ ID NO: 1894 Bac2565 RRAAVRLIVIRR SEQ ID NO: 1895 Bac2566 RRAAVSLIVIRR SEQ ID NO: 1896 Bac2567 RRAAVTLIVIIZR SEQ ID NO: 1897 Bac2568 RRAAVWLIVIRR SEQ ID NO: 1898 Bac2569 RRAAVYLIVIRR SEQ ID NO: 1899 Bac2570 RRAAVVAIVIRR SEQ ID NO: 1900 Bac2571 RRAAVVCIVIRR SEQ ID NO: 1901 Bac2572 RRAAVVDIVIRR SEQ ID NO: 1902 Bac2573 RRAAVVEIVIRR SEQ ID NO: 1903 Bac2574 RRAAVVFIVIRR SEQ ID NO: 1904 Bac2575 RRAAVVGIVIRR SEQ ID NO: 1905 Bac2576 RRAAVVHIVIRR SEQ ID NO: 1906 Bac2577 RRAAVVIIVIRR SEQ ID NO: 1907 Bac2578 RRAAVVKIVIRR SEQ ID NO: 1908 Bac2579 RRAAVVMIVIRR SEQ ID NO: 1909 Bac2580 RRAAVVNIVIRR SEQ ID NO: 1910 Bac2581 RRAAVVPIVIRR SEQ ID NO: 1911 Bac2582 RRAAVVQIVIRR SEQ ID NO: 1912 Bac2583 RRAAVVRIVIRR SEQ ID NO: 1913 Bac2584 RRAAVVSIVIRR SEQ ID NO: 1914 Bac2585 RRAAVVTIVIRR SEQ ID NO: 1915 Bac2586 RRAAVVVIVIRR SEQ ID NO: 1916 Bac2587 RRAAVVWIVIRR SEQ ID NO: 1917 Bac2588 RRAAVVYIVIRR SEQ ID NO: 1918 Bac2589 RRAAVVLAVIRR SEQ ID NO: 1919 Bac2590 RRAAVVLCVIRR SEQ ID NO: 1920 Bac2591 RRAAVVLDVIRR SEQ ID NO: 1921 Bac2592 RRAAVVLEVIRR SEQ ID NO: 1922 Bac2593 RRAAVVLFVIRR SEQ ID NO: 1923 Bac2594 RRAAVVLGVIRR SEQ ID NO: 1924 Bac2595 RRAAVVLHVIRR SEQ ID NO: 1925 Bac2596 RRAAVVLKVIRR SEQ ID NO: 1926 Bac2597 RRAAVVLLVIRR SEQ ID NO: 1927 Bac2598 RRAAVVLMVIRR SEQ ID NO: 1928 Bac2599 RRAAVVLNVIRR SEQ ID NO: 1929 Bac2600 RRAAVVLPVIRR SEQ ID NO: 1930 Bac2601 RRAAVVLQVIRR SEQ ID NO: 1931 Bac2602 RRAAVVLRVIRR SEQ ID NO: 1932 Bac2603 RRAAVVLSVIRR SEQ ID NO: 1933 Bac2604 RRAAVVLTVIRR SEQ ID NO: 1934 Bac2605 RRAAVVLVVIRR SEQ ID NO: 1935 =
Bac2606 RRAAVVLWVIRR SEQ ID NO: 1936 Bac2607 RRAAVVLYVIl2R SEQ ID NO: 1937 Bac2608 RRAAVVLIAIRR SEQ ID NO: 1938 Bac2609 RRAAVVLICIRR SEQ ID NO: 1939 Bac2610 RRAAVVLIDIRR SEQ ID NO: 1940 Bac2611 RRAAVVLIEIRR SEQ ID NO: 1941 Bac2612 RRAAVVLIFIRR SEQ ID NO: 1942 Bac2613 RRAAVVLIGIRR SEQ ID NO: 1943 Bac2614 RRAAVVLIHIRR SEQ ID NO: 1944 Bac2615 RRAAVVLIIIRR SEQ ID NO: 1945 Bac2616 RRAAVVLIKIRR SEQ ID NO: 1946 Bac2617 RRAAVVLILIRR SEQ ID NO: 1947 Bac2618 RRAAVVLIMIRR SEQ ID NO: 1948 Bac2619 RRAAVVLINIRR SEQ ID NO: 1949 Bac2620 RRAAVVLIPIRR SEQ ID NO: 1950 Bac2621 RRAAVVLIQIRR SEQ ID NO: 1951 Bac2622 RRAAVVLIRIRR SEQ ID NO: 1952 Bac2623 RRAAVVLISIRR SEQ ID NO: 1953 Bac2624 RRAAVVLITIRR SEQ ID NO: 1954 Bac2625 RRAAVVLIWIRR SEQ ID NO: 1955 Bac2626 RRAAVVLIYIRR SEQ ID NO: 1956 Bac2627 RRAAVVLIVARR SEQ ID NO: 1957 Bac2628 RRAAVVLIVCRR SEQ ID NO: 1958 Bac2629 RRAAVVLIVDRR SEQ ID NO: 1959 Bac2630 RRAAVVLIVERR SEQ ID NO: 1960 Bac2631 RRAAVVLIVFRR SEQ ID NO: 1961 Bac2632 RRAAVVLIVGRR SEQ ID NO: 1962 Bac2633 RRAAVVLIVHRR SEQ ID NO: 1963 Bac2634 RRAAVVLIVKRR SEQ ID NO: 1964 Bac2635 RRAAVVLIVLRR SEQ ID NO: 1965 Bac2636 RRAAVVLIVMRR SEQ ID NO: 1966 Bac2637 RRAAVVLIVNRR SEQ ID NO: 1967 Bac2638 RRAAVVLIVPRR SEQ ID NO: 1968 Bac2639 RRAAVVLIVQRR SEQ ID NO: 1969 Bac2640 RRAAVVLIVRRR SEQ ID NO: 1970 Bac2641 RRAAVVLIVSRR SEQ ID NO: 1971 Bac2642 RRAAVVLIVTRR SEQ ID NO: 1972 Bac2643 RRAAVVLIVVRR SEQ II) NO: 1973 Bac2644 RRAAVVLIVWRR SEQ ID NO: 1974 Bac2645 RRAAVVLIVYRR SEQ ID NO: 1975 Bac2646 RRAAVVLIVIAR SEQ ID NO: 1976 Bac2647 RRAAVVLIVICR SEQ ID NO: 1977 Bac2648 RRAAVVLIVIDR SEQ ID NO: 1978 Bac2649 RRAAVVLIVIER SEQ ID NO: 1979 Bac2650 RRAAVVLIVIFR SEQ ID NO: 1980 Bac2651 RRAAVVLIVIGR SEQ ID NO: 1981 Bac2652 RRAAVVLIVIHR SEQ ID NO: 1982 Bac2653 RRAAVVLIVIIR SEQ ID NO: 1983 Bac2654 RRAAVVLIVIKR SEQ ID NO: 1984 Bac2655 RRAAVVLIVILR SEQ ID NO: 1985 Bac2656 RRAAVVLIVIMR SEQ ID NO: 1986 Bac2657 RRAAVVLIVINR SEQ ID NO: 1987 Bac2658 RRAAVVLIVIPR SEQ ID NO: 1988 Bac2659 RRAAVVLIVIQR SEQ ID NO: 1989 Bac2660 RRAAVVLIVISR SEQ ID NO: 1990 Bac2661 RRAAVVLIVITR SEQ ID NO: 1991 Bac2662 RRAAVVLIVIVR SEQ ID NO: 1992 Bac2663 RRAAVVLIVIWR SEQ ID NO: 1993 Bac2664 RRAAVVLIVIYR SEQ ID NO: 1994 Bac2665 RRAAVVLIVIRA SEQ ID NO: 1995 Bac2666 RRAAVVLIVIRC SEQ ID NO: 1996 Bac2667 RRAAVVLIVIRD SEQ ID NO: 1997 Bac2668 RRAAVVLIVIRE SEQ ID NO: 1998 Bac2669 RRAAVVLIVIRF SEQ ID NO: 1999 Bac2670 RRAAVVLIVIRG SEQ ID NO: 2000 Bac2671 RRAAVVLIVIRH SEQ ID NO: 2001 Bac2672 RRAAVVLIVIRI SEQ ID NO: 2002 Bac2673 RRAAVVLIVIRK SEQ ID NO: 2003 Bac2674 RRAAVVLIVIRL SEQ ID NO: 2004 Bac2675 RRAAVVLIVIRM SEQ ID NO: 2005 Bac2676 RRAAVVLIVIRN SEQ ID NO: 2006 Bac2677 RRAAVVLIVIRP SEQ ID NO: 2007 Bac2678 RRAAVVLIVIRQ SEQ ID NO: 2008 Bac2679 RRAAVVLIVIRS SEQ ID NO: 2009 Bac2680 RRAAVVLIVIRT SEQ ID NO: 2010 Bac2681 RRAAVVLIVIRV SEQ ID NO: 2011 Bac2682 RRAAVVLIVIRW SEQ ID NO: 2012 Bac2683 RRAAVVLIVIRY SEQ ID NO: 2013 Bac2684 AIWVIWRR SEQ ID NO: 2014 Bac2685 CIWVIWRR SEQ ID NO: 2015 Bac2686 DIWVIWRR SEQ ID NO: 2016 Bac2687 EIWVIWRR SEQ ID NO: 2017 Bac2688 FIWVIWRR SEQ ID NO: 2018 Bac2689 GIWVIWRR SEQ ID NO: 2019 Bac2690 HIWVIWRR SEQ ID NO: 2020 Bac2691 IIWVIWRR SEQ ID NO: 2021 Bac2692 KIWVIWRR SEQ ID NO: 2022 Bac2693 LIWVIWRR SEQ ID NO: 2023 Bac2694 MIWVIWRR SEQ ID NO: 2024 Bac2695 NIWVIWRR SEQ ID NO: 2025 Bac2696 PIWV1WRR SEQ ID NO: 2026 Bac2697 QIWVIWRR SEQ ID NO: 2027 Bac2698 SIWVIWRR SEQ ID NO: 2028 Bac2699 TIWVIWRR SEQ ID NO: 2029 Bac2700 VIWVIWRR SEQ ID NO: 2030 Bac2701 WIWVIWRR SEQ ID NO: 2031 Bac2702 YIWVIWRR SEQ ID NO: 2032 Bac2703 RAWVIWRR SEQ ID NO: 2033 Bac2704 RCWVIWRR SEQ ID NO: 2034 Bac2705 RDWVIWRR SEQ ID NO: 2035 Bac2706 REWVIWRR SEQ ID NO: 2036 Bac2707 RFWVIWRR SEQ ID NO: 2037 Bac2708 RGWVIWRR SEQ ID NO: 2038 Bac2709 RHWVIWRR SEQ ID NO: 2039 Bac2710 RKWVIWRR SEQ ID NO: 2040 Bac2711 RLWVIWRR SEQ ID NO: 2041 Bac2712 RIVIWVIWRR SEQ ID NO: 2042 Bac2713 RNWVIWRR SEQ ID NO: 2043 Bac2714 RPWVIWRR SEQ ID NO: 2044 Bac2715 RQWVIWRR SEQ ID NO: 2045 Bac2716 RRWVIWRR SEQ ID NO: 2046 Bac2717 RSWVIWRR SEQ ID NO: 2047 Bac2718 RTWVIWRR SEQ ID NO: 2048 Bac2719 RVWVIWRR SEQ ID NO: 2049 Bac2720 RWWVIWRR SEQ ID NO: 2050 Bac2721 RYWVIWRR SEQ ID NO: 2051 Bac2722 RIAVIWRR SEQ ID NO: 2052 Bac2723 RICVIWRR SEQ ID NO: 2053 Bac2724 RIDVIWRR SEQ ID NO: 2054 Bac2725 RIEVIWRR SEQ ID NO: 2055 Bac2726 RIFVIWRR SEQ ID NO: 2056 Bac2727 RIGVIWRR SEQ ID NO: 2057 Bac2728 RIHVIWRR SEQ ID NO: 2058 Bac2729 RIIVIWRR SEQ ID NO: 2059 Bac2730 RIKVIWRR SEQ ID NO: 2060 Bac2731 RILVIWRR SEQ ID NO: 2061 Bac2732 RIMVIWRR SEQ ID NO: 2062 Bac2733 RINVIWRR SEQ ID NO: 2063 Bac2734 RIPVIWRR SEQ ID NO: 2064 Bac2735 RIQVIWRR SEQ ID NO: 2065 Bac2736 RIRVIWRR SEQ ID NO: 2066 Bac2737 RISVIWRR SEQ ID NO: 2067 Bac2738 RITVIWRR SEQ ID NO: 2068 Bac2739 RIVVIWRR SEQ ID NO: 2069 Bac2740 RIYVIWRR SEQ ID NO: 2070 Bac2741 RIWAIWRR SEQ ID NO: 2071 Bac2742 RIWCIWRR SEQ ID NO: 2072 Bac2743 RIWMIWRR SEQ ID NO: 2073 Bac2744 RIVVEIWRR SEQ ID NO: 2074 Bac2745 RIWFIWRR SEQ ID NO: 2075 Bac2746 RIWGIWRR SEQ ID NO: 2076 Bac2747 RIWHIWRR SEQ ID NO: 2077 Bac2748 RIWIIWRR SEQ ID NO: 2078 Bac2749 RIWKIWRR SEQ ID NO: 2079 Bac2750 RIWLIWRR SEQ ID NO: 2080 Bac2751 RIWMIWRR SEQ ID NO: 2081 Bac2752 RIWNIWRR SEQ ID NO: 2082 Bac2753 RIWPIWRR SEQ ID NO: 2083 Bac2754 RIWQIWRR SEQ ID NO: 2084 Bac2755 RIWRIWRR SEQ ID NO: 2085 Bac2756 RIWSIWRR SEQ ID NO: 2086 Bac2757 RIWTIWRR SEQ ID NO: 2087 Bac2758 RIWWIWRR SEQ ID NO: 2088 Bac2759 RIWYIWRR SEQ ID NO: 2089 Bac2760 RIWVAWRR SEQ ID NO: 2090 Bac2761 RIWVCWRR SEQ ID NO: 2091 Bac2762 RIWVDWRR SEQ ID NO: 2092 Bac2763 RIWVEWRR SEQ ID NO: 2093 Bac2764 RIWVFWRR SEQ ID NO: 2094 Bac2765 RIWVGWRR SEQ ID NO: 2095 Bac2766 RIWVHWRR SEQ ID NO: 2096 Bac2767 RIWVKWRR SEQ ID NO: 2097 Bac2768 RIWVLWRR SEQ ID NO: 2098 Bac2769 RIWVMWRR SEQ ID NO: 2099 Bac2770 RIWVNWRR SEQ ID NO: 2100 Bac2771 RIWVPWRR SEQ ID NO: 2101 Bac2772 RIWVQWRR SEQ ID NO: 2102 Bac2773 RIWVRWRR SEQ ID NO: 2103 Bac2774 RIWVSWRR SEQ ID NO: 2104 Bac2775 RIWVTWRR SEQ ID NO: 2105 Bac2776 RIWVVWRR SEQ ID NO: 2106 Bac2777 RIWVWWRR SEQ ID NO: 2107 Bac2778 RIWVYWRR SEQ ID NO: 2108 Bac2779 RIWVIARR SEQ ID NO: 2109 Bac2780 RIWVICRR SEQ ID NO: 2110 Bac2781 RIWVIDRR SEQ ID NO: 2111 Bac2782 RIWVIERR SEQ ID NO: 2112 Bac2783 RIWVIFRR SEQ ID NO: 2113 Bac2784 RIWVIGRR SEQ ID NO: 2114 Bac2785 RIWVIHRR SEQ ID NO: 2115 Bac2786 RIWVIIRR SEQ ID NO: 2116 Bac2787 RIWVIKRR SEQ ID NO: 2117 Bac2788 RIWVILRR SEQ ID NO: 2118 Bac2789 RIWVIMRR SEQ ID NO: 2119 Bac2790 RIWVINRR SEQ ID NO: 2120 Bac2791 RIWVIPRR SEQ ID NO: 2121 Bac2792 RIWVIQRR SEQ ID NO: 2122 Bac2793 RI.WVIRRR SEQ ID NO: 2123 Bac2794 RIWVISRR SEQ ID NO: 2124 Bac2795 RIWVITRR SEQ ID NO: 2125 Bac2796 RIWVIVRR SEQ ID NO: 2126 Bac2797 RIWVIYRR SEQ ID NO: 2127 Bac2798 RIWVIWAR SEQ ID NO: 2128 Bac2799 RIVWIWCR SEQ ID NO: 2129 Bac2800 RIWVIWDR SEQ ID NO: 2130 Bac2801 RIWVIWER SEQ ID NO: 2131 Bac2802 RIWVIWFR SEQ ID NO: 2132 Bac2803 RIWVIWGR SEQ ID NO: 2133 Bac2804 RIWVIWHR SEQ ID NO: 2134 Bac2805 RIVWIWIR SEQ ID NO: 2135 Bac2806 RIWVIWKR SEQ ID NO: 2136 Bac2807 RIWVIWLR SEQ ID NO: 2137 Bac2808 RIWVIWMR SEQ ID NO: 2138 Bac2809 RIWVIWNR SEQ ID NO: 2139 Bac2810 RIWVIWPR SEQ ID NO: 2140 Bac2811 RIWVIWQR SEQ ID NO: 2141 Bac2812 RIWVIWSR SEQ ID NO: 2142 Bac2813 RIVWIWTR SEQ ID NO: 2143 Bac2814 RIWVIWVR SEQ ID NO: 2144 Bac2815 RIWVIWWR SEQ ID NO: 2145 Bac2816 RIWVIWYR SEQ ID NO: 2146 Bac2817 RIWVIWRA SEQ ID NO: 2147 Bac2818 RIWVIWRC SEQ ID NO: 2148 Bac2819 RIWVIWRD SEQ ID NO: 2149 Bac2820 RIWVIWRE SEQ ID NO: 2150 Bac2821 RIWVIWRF SEQ ID NO: 2151 Bac2822 RIWVIWRG SEQ ID NO: 2152 Bac2823 RIWVIWRH SEQ ID NO: 2153 Bac2824 RIWVIWRI SEQ ID NO: 2154 Bac2825 RIWVIWRK SEQ ID NO: 2155 Bac2826 RIWVIWRL SEQ ID NO: 2156 Bac2827 RIWVIWRM SEQ ID NO: 2157 Bac2828 RIWVIWRN SEQ ID NO: 2158 Bac2829 RIWVIWRP SEQ ID NO: 2159 Bac2830 RIWVIWRQ SEQ ID NO: 2160 Bac2831 RIWVIWRS SEQ ID NO: 2161 Bac2832 RIWVIWRT SEQ ID NO: 2162 Bac2833 RIWVIWRV SEQ ID NO: 2163 Bac2834 RIWVIWRW SEQ ID NO: 2164 Bac2835 RIWVIWRY SEQ ID NO: 2165 [0164] Circular dichroism (CD) spectroscopy. CD spectra were recorded using a Jasco J-810 spectropolarimeter (Japan). Spectra were measured using a quartz cell with 1 mm path length at room temperature between 190 and 250 nm at a scan speed of lOnm/min and a total of 10 scans per sample. The data were collected and processed by the manufacturer's software. The concentration for each peptide was 70 M.
Spectra were recorded in 100 mM Tris buffer, pH 7.3, 10mM sodium dodecyl sulphate (SDS), or liposomes made by extrusion of 1:1 mixtures of 1-palmitoyl-2-oleoyl-sn-glycero-phosphocholine (POPC) and 1-1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG). In all cases, the spectrum of the buffer only was subtracted from the peptide spectra.
[0165] Minimal inhibitory concentration (MIC) determination. The MICs of the peptides were measured using a modified broth microdilution method in Mueller Hinton (MH) medium. Wu et al., J. Biol. Chem. 274: 29-35, 1999. Briefly, the peptides were dissolved and stored in glass vials. The assay was performed in sterile 96-well polypropylene microtitre plates were used. Serial dilutions of the peptides to be assayed were performed in 0.01% acetic acid (Fisher) containing 0.2% bovine serum albumin (Boehringer Mannheim GmbH) at lOX the desired final concentration. Ten microlitres of the lOX peptides were added to each well of a 96-well polypropylene plate containing 90 l of MH media per well. Bacteria were added to the plate from an overnight culture at 2 -7 x 105 colony forming units/ml and incubated over night at 37 C. The MIC was taken as the concentration at which no growth was observed.
[0166] Luminescence-based MIC assay for the non-cleaved peptides on cellulose membranes. The peptide spots were punched out and transferred to a 96 well microtiter plate with a clear polystyrene bottom and opaque white polypropylene sides (PerkinElmer, Boston, USA). The spots were washed two times with 100% ethanol for 5 min and afterwards equilibrated five times with 100 mIVI Tris buffer pH 7.3 for 5 min.
An overnight culture of Pseudomonas aeruginosa strain H100 1 fliC:: luxCDABE was diluted 1:50 in new MH medium and incubated at 37 C to an OD600 of 0.35. This bacterial culture was diluted 1:25 into 100mM Tris-HCl buffer, pH 7.3 containing 20 mM
glucose.
Fifty l of this culture was added to all wells of the microtiter plate and incubated at 37 C.
The luminescence of the strain produced by the ATP-dependent luciferase system was detected in a time dependent manner using a Tecan Spectra Fluor plus (Tecan, Austria). At the end of the experiment, the membranes were cleaned by washing the spots two times with 100% ethanol for five minutes. After removing the ethanol the membrane was air-dried.
[0167] Assay for the cleaved peptides from cellulose support. The peptides were cleaved from the dried membrane in an ammonia atmosphere overnight, resulting in free peptides with an amidated C-terminus. The free peptides contained two 0-alanines at the C-terminus, in addition to being amidated due to the linker between the cellulose membrane and the peptide sequence. The peptide spots were punched out and transferred in a 96-well microtiter plate. Serial dilutions were carried out from the membrane spots.
Four rows were filled with four controls including two with Bac2A and two with of an unrelated peptide. The other eight rows were used for serial dilution steps of the peptide variants. An overnight culture of Pseudomonas aeruginosa strain H1001 was diluted 1:500 using either LB media or 100mM Tris buffer pH 7.3, 20mM glucose and was added to the wells (100 l/well) containing the peptide spots. In all other wells 50 l were added.
The microtiter plate was,incubated for 30 min at 37 C to release the peptides from the membrane. Subsequently, a dilution series were performed and the plate was incubated at 37 C. The luminescence produced by the ATP dependent luciferase system were detected in a time dependent manner using a Tecan Spectra Fluor plus.
[0168] LPS Binding and Cytotoxicity assay. Peptides are known to bind to bacterial lipopolysaccharide as part of their mechanism of action and this binding can be revealed through the ability of the peptide to inhibit the ability of the peptide to suppress the production of TNFa by monocytic cells such as the human monocyte cell line cells (Fig. 8). THP1 cells were cultured in RPMI 1640 medium (supplemented with 10%
(v/v) FCS, 1% L-glutamine, and 1 nM sodium pyruvate) in E-toxa-clean (Sigma-Aldrich, Oakville, Ontario, Canada)-washed, endotoxin-free bottle. THP1 cells were counted and 250 1 per well of 2-4 x 104 cells/ml were transferred into a 96 well tissue cultured treated polystyrene microtiterplate (Beckton Dickinson, Franklin Lakes, USA). In addition PMA
was added (1.3 nM) and the cells were incubated for three days. After three days the medium were exchanged and Pseudomonas aeruginosa LPS and the peptides were added.
The incubation time was four hours and the supernatant was frozen at -20 C.
The cells were stained with Tryphan Blue for 2 minutes and washed with PBS two times.
The viability of the cells was determined by counting the stained cells over the unstained. The supematant was used to measure the TNFa production by an ELISA (eBioscience, SanDiego, USA) following the manufactures protocol (Fig. 8).
[0169] Strains. For the killing assay a mini-Tn5-lux mutant in Pseudomonas aeruginosa H103 was used. The strain is called H1001 and contains a fliC::luxCDABE
transcriptional fusion resulting in constitutive expression of luciferase. The bacterial strains used for the antimicrobial activity assays included Escherichia coli UB 1005 (F-, nalA37, metB1), a wild-type Salmonella enterica ssp. Typhimurium (S.
Typhimurium), wild-type Pseudomonas aeruginosa PAO1 strain H103, Enterococcusfaecalis ATCC29212, Staphylococcus aureus ATCC25923, and a clinical isolate of Staphylococcus epidermidis obtained from Dr. D. Speert (Department of Medicine, University of British Columbia). Antifungal activity was tested using a lab isolate of Candida albicans obtained from Dr. B. Dill (Department of Microbiology and Immunology, University of British Columbia).

Scrambled Peptides [0170] Bac2A is a short peptide of 12 amino acids with a maximal length of about 40A. This peptide can kill both Gram positive and Gram negative bacteria. To learn more about the relationships between structure and activity, 49 scrambled variants of Bac2A were synthesized. All these peptides have the same length, same net charge and same amount of hydrophilic and hydrophobic amino acids.
[0171] Peptide synthesis on cellulose is a very effective and inexpensive way to investigate many different peptide variants for one particular activity.
However, one of the problems of this technique is the low peptide density synthesized on the membrane, about 280 nmol per cm2. An average peptide spot used for the experiments presented is about 0.3 cm2. Therefore, an assay had to be developed that was sensitive enough to show activity with this amount of peptides. P. aeruginosa H1001 has a reporter system (e.g., a luciferase gene cassette) incorporated into the bacterial chromosome in thefliC gene (involved in flagellar biosynthesis) that is constitutively expressed. It will thus produce light if ATP is present. When this strain is killed, e.g. by peptides, the amount of light produced will decrease due to a decrease in ATP levels in the killed cells.
This action can thus be monitored by detecting luminescence in a microtiter plate luminescence reader over time. The volume and amount of cells per well were optimized for this assay. After screening, the killing action was monitored with small amounts of the parent peptide Bac2A (2 g/ml of free peptide). Control experiments demonstrated that the decrease in luminescence (Fig. 1A) reflected bacterial death as assessed by the loss of colony forming ability (Fig. 1B) [0172] Forty-nine scrambled peptides (Bac002-Bac050) were synthesized on the cellulose support and then cleaved by ammonia gas resulting in free peptides with an amidated C-terminus including the linker. The peptide spots were transferred to a 96-well microtiter plate and incubated for 30 min to dissociate the peptides from the cellulose.
After serial dilution and addition of strain H1001, luminescence was recorded in a time dependent manner (Fig. 1). A1150 scrambled peptides were compared to Bac2A
(RLARIVVIRVAR-NH2; SEQ ID NO: 1) by this assay (see Table 2). Each of the peptides showed some killing activity against P. aeruginosa strain H1001 at the highest concentration, in contrast to the unrelated negative-control peptide (GATPEDLNQKLS;
SEQ ID NO: 321). Only two peptides showed decreased activity at the highest concentration. This data indicates that the ability of the short peptides to kill Pseudomonas aeruginosa strain is determined by the general properties of amino acid domains rather than the composition of the amino acids that was the same for each peptide.
Further since all scrambled peptides had some activity, a sequence-specific interaction of the peptides with a receptor or target could be excluded.
[0173] The same set of peptides, as well as the reversed sequence of Bac2A-R
(RAVRIVVIRALR; SEQ ID NO: 2166), were synthesized on cellulose and left uncleaved.
The production of light was initially compared in wells containing spots of Bac2A, Bac2A-R (with the reversed sequence of Bac2A), the unrelated negative-control peptide, or, as additional controls, only cellulose, or only bacteria (Fig. 2). The reversed Bac2A
sequence showed only a slightly decreased ability to inhibit light production, while the control wells demonstrated no activity in decreasing luminescence.
[0174] To rule out the possibility that the non-cleaved peptides were being released from the membrane during the assay, a similar assessment of killing with four separate peptide spots (two containing Bac2A and two containing the unrelated peptide) was reiterated 10 times. Thus the peptide spots, after addition to the wells of the microtiter plate, were incubated through 10 consecutive identical cycles comprising exposure for 40 h to bacteria, followed by 14 h of exposure to 96% ethanol and 4 h of washing with Tris-HCI, pH 7.5 buffer. For each cycle, very similar inhibition of light production (killing) was observed. This is strong evidence that the observed killing is not a result of cleavage of the peptides from the membrane.
[0175] The complete set of scrambled peptides was measured in one experiment in a 96-well plate with the results shown in Table 3. The data shows that uncleaved cellulose bound peptides are able to kill P. aeruginosa strain H1001. As a control, the negative control (unrelated) peptide Bac429 and parent peptide Bac2A (=
Bac001) were used in several different wells of the microtiter plate. Luminescence (relative light units;
RLU) was measured at 14 different time points, 9 of which are shown. To permit comparison of the data with the free peptide data set, the result for each peptide was classified into six different groups, like the data set with the free peptides (Table 2). As shown in Table 2, measurement of the killing activity of scrambled peptides with soluble and bound peptides is listed according to relative activity classes of the free peptides and compared to Bac2. For the soluble peptides the following classes were established:

[0176] Class 1: Peptides showing stronger killing than Bac2A at a 4 to 8-fold higher dilution;
[0177] Class 2: Peptides showing stronger killing compared to that of Bac2A at a 4-fold higher dilution;
[0178] Class 3: Peptides similar to Bac2A;
[0179] Class 4: Peptides similar to Bac2A at the highest concentration but demonstrating weaker killing at a 2-fold dilution;
[0180] Class 5: Peptides giving very weak or no killing at a 2-fold dilution;
and [0181] Class 6: Peptides with weak killing activity at the highest concentration.
[0182] For the uncleaved peptides the following classes were established:
[0183] Class 1: Peptides reducing luminescence (lux) values to less than 500 after 40 min.;
[0184] Class 2: Peptides reducing lux values to between 500 and 1000 after 40 min.;
[0185] Class 3: Peptides similar to Bac2A resulting in lux values of less than 500 after 240 min.;
[0186] Class 4: Peptides reducing luminescence (lux) values to between 500 to 1499 after 240 min.;
[0187] Class 5: Peptides reducing luminescence (lux) values to between 1500 to 3000 after 240 min.; and [0188] Class 6: Peptides having residual luminescence (lux) values greater than 3000 after 240 min.
[0189] The correlation of the numbers within the classification groups of bound and soluble peptides variants was strong with only 14 peptides (28%) demonstrating differences of 2 classes or more between the bound and soluble forms. However there was a general trend amongst all of the peptides towards decreasing activity for the bound versions. Only two free peptides were classified into group 6 compared to 10 bound peptides. The opposite was true in classes 1 and 2 for which there were reduced numbers of bound peptides. Only three bound peptides were more active than Bac2A in contrast to free peptides, possibly due to restrictions on the conformational freedom of these C-terminally bound peptides.

[0190] An analysis was performed in an attempt to understand the basis for differing activity of the scrambled peptides. No correlation was observed between the sequence and the activity, and no sub-sequences corresponding to improved activity were observed. This result strengthens the concept that there are no sequence-specific interactions involved in killing bacteria. Computational analysis was therefore performed to identify any general structural features which might correlate with activity, using a series of descriptors of peptide structure. There was no correlation between the position of arginines in the peptides and the activity. A good correlation between activity and the existence of a hydrophobic patch of 5, or more, consecutive hydrophobic amino acid residues was determined.
[0191] Five of the most active Class 1 (free) peptides and two of the least active Class 6 (free) peptides were chosen to confirm the screening methods and to permit more detailed investigations. In addition, the parent peptide Bac2A was included in these studies as a standard. The minimal inhibitory concentrations (MIC) were determined for the important medical pathogens Pseudomonas aeruginosa, Escherichia coli, Salmonella typhimurium, Staphylococcus aureus, Staplzylococcus epidermidis, Enterococcus faecaelis, and the yeast Candida albicans in Mueller-Hinton media. The measured MIC
values (averages of three independent measurements are shown in Tables 4a and 4b) for this broader spectrum of organisms reflected very well the classification of the free peptides as recorded in Table 2. All class 1 peptides showed lower MICs (better activity) than Bac2A, with the best being about seven times more active. The two class 6 peptides showed an MIC that was at least 5 times higher (worse) than that for Bac2A.
Two of the peptides from class 1 demonstrated low solubility in water and were not used for further investigations. The MICs for P. aeruginosa exposed to high and low Mg2+
conditions demonstrated the same 4-fold difference in MIC for both Bac2A and the class 1 peptides (Table 5).
[0192] To determine if the activity of the scrambled peptide variants reflected structural differences, CD spectroscopic measurements were performed in Tris buffer, with SDS and with liposomes (Fig. 3A-C). All of the peptides had a typical random structure in Tris buffer. In the membrane-mimicking detergent SDS, the peptides showed spectra with characteristics of 0-sheet conformations. The only exception was peptide 44 (class 6), which displayed a spectra that was more helical in nature. As SDS
is an artificial membrane mimetic experiments were performed using liposomes, to directly assess the influence of lipids on structure. In liposomes, the Class 1 peptides again demonstrated spectra typical of (3-structures, whereas both Class 6 peptides displayed more unstructured spectral characteristics. This suggests that those peptides with low antimicrobial activity are less able to interact with membranes resulting in structural changes. This strongly suggests that these structural attributes are correlated with the antimicrobial activity.
[0193] The ability to depolarize the membrane of Gram-positive bacteria can be monitored by the release of the fluorescent dye diSC35 (Fig. 4). The peptide Bac2A and all Class 1 peptides were able to depolarize the membrane of S. aureus very quickly, with similar rates as gramicidin S, see Fig. 4. In contrast, the Class 6 peptides showed a lower ability to depolarize the membrane. Cytotoxicity was assessed using PMA-treated, human macrophage THP-1 cell line (Fig. 5). All tested scrambled peptides showed no cytotoxicity and indeed a lower cytotoxic effect on THP-1 cells than either B
ac2A or the human host defence peptide LL-37.
[0194] The best peptide variant, Bac020, was found to have a very low MIC (7 g/ml) against P. aeruginosa and other bacteria, compared to the parent molecule Bac2A
and had no cytotoxic effect at 100 g/m1 against a human macrophage cell line.
The discovery of this and other improved peptide variants shows the advantage of using high-throughput solid-phase methodology in the discovery of antimicrobial peptides with improved activity.

Activit Class Difference in Class Peptide Sequence Soluble bound Soluble - Bound Bac006 VRIRARRVILVA 1 3 -2 BacOlO AAVRRRVRLVII 1 3 -2 Bac014 RAVAVIIRLRRV 1 nd Bac020 RRAAVVLIVIRR 1 1 0 Bac034 VRLRIRVAVIRA 1 3 -2 Bac043 RVLIVIRARRVA 1 3 -2 Bac008 VLIRIRRVARAV 2 5 -3 Bac016 RARIVRVRVILA 2 3 -1 Bac018 RRVAIVVIARLR 2 2 0 Bac029 IILAVRAVRRVR 2.5 4 -1.5 BacOOl RLARIVVIRVAR 3 3 0 Bac002 RRIARVIVAVLR 3 3 0 Bac004 IRARIAVRRVVL 3 5 -2 Bac005 IVRVAVALRRIR 3 5 -2 Bac012 IAARRLIRVVRV 3 6 -3 Bac013 VARIVVRLIRAR 3 3 0 Bac015 AVRAIRVLRVIR 3 4 -1 Bac025 ARAILIRVVRRV 3 3 0 Bac026 IARRIVAVRLRV 3 3 0 Bac042 ILVIVRRRARAV 3 3 0 Bac045 VIALRIAVRRVR 3 3 0 Bac046 RRRVIVAVLARI 3 3 0 Bac047 RVLIAARVIRRV 3 5 -2 Bac049 VIALVRARVRRI 3 5 -2 Bac050 RRVIAIAVRRLV 3 6 -3 Bac007 RRLVAIVAVRRI 4 3 1 BacOll AVRVRRRAILVI 4 3 1 Bac021 ARIARRVRILVV 4 3 1 Bac024 RAIIRRVLVRVA 4 4 0 Bac032 ARRARIRILVVV 4 3 1 Bac036 RARRVRVLIAIV 4 3 1 Bac037 RAIRVRRIVLAV 4 3 1 Bac041 RLRVAIVAIVRR 4 2 2 Bac048 VVRALRRIIARV 4 6 -2 Bac023 RRRAIVRVVAIL 4.5 3 1.5 Bac030 IVVRRRRAALVI 4.5 6 -1.5 Bac003 ARRLIVRVRVIA 5 3 2 Bac009 IIRAALRRVRVV 5 6 -1 Bac017 VILARRRVRIAV 5 3 2 Bac019 ILVARVIRRRVA 5 5 0 Bac028 VIVRLAARRVRI 5 6 -1 Bac031 LAIVRRARVRIV 5 6 -1 Bac033 IRVRRLVAAVIR 5 5 0 Bac035 RVLRVVRAAIRI 5 5 0 Bac038 VVIRAAIRRVRL 5 5 0 Bac039 RIVLRRAAVIRV 5 6 -1 Bac040 VLARVVARRIRI 5 5 0 Bac027 RVLIARVVRAIR 5.5 6 -0.5 Bac022 ILRRVRVRAVAI 6 5 1 Bac044 VIRRRRILAAVV 6 6 0 Luniinescence at the given time in minutes Peptide 0 20 40 60 80 100 120 180 240 Bac429 4537 7275 6459 6149 6092 5799 5611 5656 5881 BacOOl 4530 6411 1840 163 88 57 84 73 52 BacOO2 4340 6090 1631 135 58 48 35 59 48 Bac003 4138 5992 3320 906 192 74 83 76 36 Bac004 3773 6547 5008 4405 3805 3125 2753 2459 2607 Bac005 3853 6844 5163 4287 3443 2254 1891 1665 1791 Bac006 3878 6829 4619 2393 867 469 277 286 306 BacOO7 3943 7157 4403 2010 679 205 90 89 79 Bac008 3718 6695 5154 4426 3671 3164 2786 2703 2890 Bac009 3935 6553 4936 4512 3977 3488 3216 3270 3104 BacOlO 4380 6719 4170 1628 562 129 121 99 56 BacOll 4516 7019 5176 3694 2076 1222 816 494 447 Bac429 4295 7478 6031 5770 5449 4779 4438 3939 3689 BacOOl 4374 6729 2607 341 96 48 112 43 45 Bac012 4045 7171 5701 5037 4631 4418 4182 4344 5087 Bac013 3890 6850 3930 1584 494 193 111 100 66 Bac014 5233 8217 7835 7867 8100 8931 8956 10738 12876 Bac015 4309 7112 5227 3783 2656 1785 1398 1244 1320 BacOl6 4172 6362 2916 678 142 80 60 68 22 Bac017 4219 7259 5041 3136 1907 1047 578 321 214 Bac018 4966 6080 981 82 44 60 62 50 39 Bac019 5239 7569 5731 4741 3822 3000 2373 1908 1570 Bac020 5285 4935 145 54 34 46 48 67 33 Bac021 5470 7247 4581 1967 683 278 196 129 128 Bac429 4593 7525 6900 6732 6701 6812 6872 7674 9094 BacOOl 4041 6352 2249 244 118 35 59 34 52 Bac022 4336 7179 5180 4505 3675 3365 3044 2912 2966 Bac023 3958 7783 5656 3751 1827 761 329 123 79 Bac024 4164 7630 5586 4358 3256 2398 1727 1384 1373 Bac025 4354 6728 3660 1127 343 113 115 114 80 Bac026 4873 6389 4439 2341 1080 518 302 201 208 Bac027 4437 6695 4991 4421 4011 3545 3100 3182 3513 Bac028 5001 6828 5315 5037 4555 4143 3762 3646 4268 Bac029 4538 6664 5062 3963 2745 1799 1279 1012 942 Bac030 4618 7325 5921 5326 4981 4418 4087 3861 3679 Bac031 4646 7357 5808 5146 4145 3815 3472 3130 3247 Bac429 4337 7118 6593 6716 6273 6453 6210 6656 7935 BacOOl 4234 6373 1840 169 73 50 48 42 20 Bac032 4649 6342 4584 2088 595 148 107 54 33 Bac033 4795 6539 4785 4155 3565 3095 2639 2613 2962 Bac034 5305 6449 4160 1454 390 157 64 60 63 Bac035 5199 6461 4989 4389 4001 3439 3162 2456 2577 Bac036 5208 7062 5114 3233 1182 394 215 129 107 Bac037 4908 6480 4105 1624 366 120 54 59 46 Bac038 5024 7158 5307 4676 4112 3323 2739 2466 2576 Bac039 4727 7074 5814 5262 4994 4717 4569 4524 5392 Bac040 4220 6241 4269 3951 3368 2880 2761 2300 2415 Bac041 4620 5674 615 54 68 37 77 53 37 Bac429 4761 7536 6318 6102 5996 6086 5899 6384 6991 BacOOl 4425 6323 2721 413 151 53 75 85 40 Bac042 5171 6703 4453 2128 746 244 86 49 52 Bac043 5254 6385 3722 1189 313 159 67 84 52 Bac044 5592 7069 5932 5652 5206 5008 4999 5060 5195 Bac045 4873 6105 2726 554 83 61 37 57 35 Bac046 4408 5904 2345 233 76 70 102 48 53 Bac047 4733 6747 5100 4770 4031 3383 3012 2829 2615 Bac048 5001 6505 5163 4406 3824 3470 3423 3268 3694 Bac049 4926 7239 5219 4106 3188 2524 2059 1687 1794 BacO5O 4803 6715 5157 4430 3915 3428 3246 3206 3590 None 5322 7699 6664 6607 6523 6427 6273 6902 6960 TABLE 4a MIC (mg/ml) Peptide Gram Negative Bacteria Yeast P.aeruginosa E. coli S. typhimurium C. albicans Bac2A 50 17 34 9 Bac006 28 12 N.D. N.D.
Bac014 33 4 11 8 Bac020 7 2 18 11 Bac022 250 38 272 272 Bac034 10 1 6 8 Bac043 40 7 N.D. N.D.
Bac044 >250 97 113 136 TABLE 4b MIC (mg/ml) Peptide Gram Positive Bacteria S. aureus S. epidermidis E. faecalis Bac2A 17 4 17 Bac006 28 N.D. N.D.
Bac014 13 8 11 Bac020 5 1.5 8 Bac022 125 136 272 Bac034 5 4 11 Bac043 23 N.D. N.D.
Bac044 250 113 >272 MIC ( /ml) P. aeYuginosa Peptide Soluble Muller Hinton With 10 M With 2 mM
Class Media Mg Mg Bac020 1 7 2 8 Bac034 1 10 4 16 Bac014 1 33 16 63 Bac2A 3 54 18 73 Bac022 6 250 250 >250 Bac044 6 >250 250 >250 Truncation Experiments [0195] Although the specific set of active peptides differed among the free and bound peptides, it is apparent that activity can be correlated with the presence of a "hydrophobic patch". The specific location of this patch (e.g., N-terminal, C-terminal or central to the sequence) was not important in either the free or bound peptide activity models, but N-terminal hydrophobicity was of central importance in the explaining the difference in activity between the soluble and bound peptides.
[0196] These conclusions were further evaluated in the context of another experiment in which the Bac2A peptide was gradually truncated and activity similarly assessed (Fig. 6). In this case, the primary predictor of activity across all the truncated enzymes (sequence length 5-12 amino acids), was the length of the peptide. No peptides of less than 8 amino acids were active in this assay (Figs. 6A and 6B). Further analysis of the peptides > 8 amino acids (10 peptides) revealed a dependence on the presence of arginine within the peptide. Measurement of MICs of these peptides against our panel of strains (Table 6) revealed moderate MICs that were generally higher (demonstrating weaker activity) than that of the parent peptide Bac2A.

Complete Substitution Analysis [0197] To analyze the positional importance of the specific amino acids in Bac2A, each amino acid was changed to the other 19 amino acids one-by-one, creating a total of 229 unique peptides. Activity was assessed in the lux-based assay (Fig. 7). The results revealed definite positional specificity of particular amino acids and many substitutions that improved the activity of Bac2A. Referring to the grid shown in Fig. 7, the top row provides the amino acid substituted for the natural residue of the parent peptide given at the start of each row. Thus, for example, the peptide in the upper left hand corner (row 1 column 1) is ALARIVVIRVAR (SEQ ID NO: 93), and the next peptide in row 1, column 2 is RCARIVVIRVAR (SEQ ID NO: 113), and so forth, whereas the peptide in row 2, colunm 1 is RAARIVVIRVAR (SEQ ID NO: 112), then in row 3, column 1 the unmutated Bac2A peptide RLARIVVIRVAR (SEQ ID NO: 1), in row 4, column 1 the peptide is RLAAIVVIRVAR (SEQ ID NO: 150), and so forth. The results are the residual luminescence after treatment of the lux reporter strain H1001 with peptide for 1 minute. Results are color coded as black = superior activity to the parent peptide Bac2A = Bac001; dark grey with white lettering = equivalent activity to the parent peptide Bac001; light grey with black lettering = inferior activity to the parent peptide Bac2A =
Bac001; white = very little activity.
[0198] The most favored residues were:
AA1 = W
AA2 = C, G, H, K, R, S, W, Y
AA3=C,F,H,I,K,L,Q,R,W
AA4 = no improvement on R
AA5 = C, R, W
AA6 = C, F, W
AA7=C,H,I,K,N,Q,R,T
AA8=C
AA9=C
AA 10 = C, W
AA11=C,G,H,I,K,L,M,R,S,Y
AA12 = no improvement on R

[0199] It is clear that some amino acids particularly C>W>R>H,K are often preferred to the parent residue. In contrast, some residues never led to an improvement in activity, namely A, D, E, P, and V. Overall substitutions were rarely conservative and predictable just from the obvious substitution of e.g. one hydrophobic residue for another.
Some positions were particularly rich candidates for substitution, namely positions 2,3,7, and 11.
[0200] Regarding unfavorable substitutions, the least favorable substitutions were:
AA1=E
AA2 = none AA3 = none AA4 = D, E, F, G, I, L
AA5 = D
AA6 = D, E, G, P
AA7 = P
AA8=I,D,E,G,N,S,T
AA9 = I, D, E, H, I, L, N, P, Q, S, V
AA10=I,D,E,G,Q,S
AAl1 = none AA12 = C, D, E, F, L, M, P, S, W, Y
[0201] Generally speaking those positions with the most favorable substitutions (AA2, AA3, AA7, and AA11) were the most flexible and had the least number of unfavorable substitutions. Five positions did not readily accept substitutions namely AA9, AA12, AA8, AA10 and AA4, and for these the parent (Bac2A) amino acid was often the best residue.
[0202] A number of these peptides were then synthesized and tested against a panel of strains (Table 6). These MIC measurements bore out the data from the spot synthesis results. Peptides shown to be better in the lux assay generally had superior MICs against the whole panel of bacteria although for 3 peptides lack of solubility was an issue.
Conversely predicted poor substitutions led to peptides that had a lower effectiveness against all bacteria (e.g., the V7P and I9F substitutions).
[0203] To see if this information could be used for improved design of peptides, new peptides were made that combined 2 to 6 of the favorable amino acid substitutions (Table 6). Dramatic improvements in activity were observed over all other peptides studied, particularly in two of the peptides that developed very broad spectrum activity.
[0204] Interestingly, the same information could be used for the truncated peptides, in this case starting from an insoluble (n.s.) 8-mer truncation derivative (SEQ ID
NO: 68), substitution of 3-4 residues led to peptides with activity equal to or better than Bac2A (Table 6). Activity of substitution peptides and truncation variants for the bacteria P. aeruginosa (P.aerug), E. coli, S. Typhimurium, S. Typhiin, S. aureus, S.
epidermidis (S.
epi), and E. faecalis, and the yeast C. albicans is shown in Table 6.

Peptide MIC ( ml) P. aerug E. coli S. Typhim. S. aureus S. epi. E.faecalis C. albicans Bac2A 50 17 34 17 4 17 9 Bac206 125 16 63 63 16 31 125 Bac225 31 8 31 31 16 31 16 Bac233 8 4 8 16 2 16 8 Bac252 8 4 8 8 2 8 16 Bac241 n.s. n.s. n.s. n.s. n.s. n.s. n.s.
Bac256 8 2 8 2 0.5 2 8 Bac263 n.s. n.s. n.s. n.s. n.s. n.s. n.s.
Bac290 63 16 31 63 16 125 125 Bac297 n.s. n.s. n.s. n.s. n.s. n.s. n.s.
Bac327 >250 250 >250 >250 >250 >250 >250 Bac323 31 16 63 125 31 125 31 Bac338 >250 >250 >250 >250 >250 >250 >250 Bac289 16 4 8 8 2 4 8 Bac404 16 8 8 8 2 8 8 Bac415 63 16 63 63 31 31 63 Bac430 2 0.5 4 2 0.2 4 4 Bac431 2 4 8 2 0.5 2 4 Bac432 31 4 16 8 1 8 31 Bac433 8 2 8 8 2 4 31 BaclOl 63 8 31 63 16 31 63 Bac102 83 42 >83 83 11 46 83 Bac103 46 23 46 46 11 23 23 Bac109 n.s. n.s. n.s. n.s. n.s. n.s. n.s.
Bac112 n.s. n.s. n.s. n.s. n.s. n.s. n.s.
Bac118 n.s. n.s. n.s. n.s. n.s. n.s. n.s.
Bac434 16 8 31 16 4 16 16 Bac435 16 4 16 4 4 8 16 Bac436 8 2 8 2 2 2 8 Bac437 250 16 31 16 8 32 63 [0205] From the foregoing description, various modifications and changes in the compositions and methods will occur to those skilled in the art. All such modifications coming within the scope of the appended claims are intended to be included therein. Each recited range includes all combinations and sub-combinations of ranges, as well as specific numerals contained therein.
[0206] All publications and patent documents cited above are hereby incorporated by reference in their entirety for all purposes to the same extent as if each were so individually denoted.
[0207] Although the foregoing invention has been described in detail by way of example for purposes of clarity of understanding, it will be apparent to the artisan that certain changes and modifications are comprehended by the disclosure and can be practiced without undue experimentation within the scope of the appended claims, which are presented by way of illustration not limitation.

Claims (36)

1. An isolated antimicrobial peptide having 8 to 12 amino acids, wherein the peptide has an amino acid sequence of SEQ ID NOS: 1-2166, or analogs, derivatives, amidated variations and conservative variations thereof.

2. An isolated polynucleotide that encodes a peptide of claim 1.

3. The peptide of claim 1 comprising any contiguous sequence of amino acids having the formula: R1-L2-A3-R4-I5-V6-V7-I8-R9-V10-A11-R12, wherein R1= R or W; L2 =
L, C, G, H, K, R, S, W, or Y; A3 = A, C, F, H, I, K, L, Q, R, or W; I5 = I, C, R, or W;
V6 = V, C, F, or W; V7 = V, C, H, I, K, N, Q, R, or T ; I8 = I or C; R9 = R or C; V10 = V, C, or W; A11=
A, C, G, H, I, K, L, M, R, S, or Y, and derivatives, substitutions, deletions and additions thereof.

4. The peptide of claim 1, wherein the peptide has an amino acid sequence having the formula: AA1 - AA2 - AA3 - AA4 - AA5 - AA6 - AA7 - AA8 - AA9 - AA10 - AA11 -AA12, wherein AA1 = A, G, I, K, L, P, R, or W; AA2 = any residue except D, E, M, or N; AA3 =
any residue; AA4 = K, M, or R; AA5 = C, I, K, R, V, or W; AA6 = C, F, K, R, V, W, or Y;
AA7 = C, F, G, H, I, K, L, N, Q, R, T, V, or Y; AA8 = C, F, I, K, R, V, W, or Y; AA9 = C, K, or R; AA10 = C, I, K, L, R, V, W, or Y; AA11 = any residue except D, E, or P; AA12 =
A, or R, and derivatives, substitutions, deletions and additions thereof.

5. The peptide of claim 1, wherein the peptide has a sequence of 8 amino acids having the formula: AA1 - AA2 - AA3 - V - I - AA6 - AA7 - R, wherein AA1 = K
or R;
AA2 = I or R; AA3 = W or V; AA6 = R or W; and AA7 = R or W.

6. A polypeptide X1- A -X2 or a functional variant or mimetic thereof, wherein A
represents at least one peptide having an amino acid sequence of SEQ ID NOS: 1-2166 or analogs, derivatives, amidated variations and conservative variations thereof;
and wherein each X1 and X2 independently of one another represents any amino acid sequence of n amino acids, n varying from 0 to 50, and n being identical or different in X1 and X2.

7. The polypeptide of claim 6 wherein the functional variant or mimetic is a conservative amino acid substitution or peptide mimetic substitution.

8. The polypeptide of claim 7 wherein the functional variant has about 70% or greater amino acid identity to X1- A -X2.

9. The polypeptide of claim 6 wherein n is zero.

10. A method of inhibiting the growth of bacteria comprising contacting the bacteria with an inhibiting effective amount of a peptide having an amino acid sequence of SEQ ID
NOS: 2-2166, or any combination thereof, or analogs, derivatives, amidated variations and conservative variations thereof, with the proviso that the peptide having an amino acid sequence of SEQ ID NO: 1 is only used in combination with any peptide having an amino acid sequence of SEQ ID NO: 2-2166.

11. The method of claim 10, wherein the bacteria is Gram positive.

12. The method of claim 11, wherein the bacteria is Staphylococcus aureus, Staphylococcus epidermidis, or Enterococcusfaecaelis.

13. The method of claim 10, wherein the bacteria Gram negative.

14. The peptide of claim 13, wherein the bacteria is Pseudomonas aeruginosa, Escherichia coli, or Salmonella enteritidis ssp Typhimurium.

15. The method of claim 10, wherein the contacting comprises a peptide in combination with at least one antibiotic or lysozome.

16. The method of claim 15, wherein the antibiotic is selected from the group consisting of aminoglycosides, penicillins, cephalosporins, carbapenems, monobactams, quinolones, tetracyclines, and glycopeptides.

17. The method of claim 16, wherein the antibiotic is selected from the group consisting of amikacin, gentamicin, kanamycin, netilmicin, tobramycin, streptomycin, azithromycin, clarithromycin, erythromycin, erythromycin estolate/ethyl-succinate/gluceptate/lactobionate/stearate, penicillin G, penicillin V, methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin, ampicillin, amoxicillin, ticarcillin, carbenicillin, mezlocillin, azlocillin, piperacillin, cephalothin, cefazolin, cefaclor, cefamandole, cefoxitin, cefuroxime, cefonicid, cefmetazole, cefotetan, cefprozil, loracarbef, cefetamet, cefoperazone, cefotaxime, ceftizoxime, ceftriaxone, ceftazidime, cefepime, cefixime, cefpodoxime, cefsulodin, imipenem, aztreonam, fleroxacin, nalidixic acid, norfloxacin, ciprofloxacin, ofloxacin, enoxacin, lomefloxacin, cinoxacin, doxycycline, minocycline, tetracycline, vancomycin, chloramphenicol, clindamycin, trimethoprim, sulfamethoxazole, nitrofurantoin, rifampin and mupirocin and teicoplanin.

18. The method of claim 10, wherein the peptide is covalently bound to a solid support.

19. The method of claim 18, wherein the solid support is a medical device.

20. A method for identifying an antimicrobial peptide having 8 to 12 amino acids comprising contacting a test peptide with a microbe under conditions sufficient for antimicrobial activity, and detecting a change in growth or proliferation of the microbe as compared to the growth or proliferation of the microbe prior to the contacting.

21. The method of claim 20, wherein the test peptide is synthesized in a multi-spot format on a solid support.

22. The method of claim 20, wherein the test peptide is covalently bound to a solid support.

23. The method of claim 22, wherein the test peptide retains antimicrobial activity when cleaved from the solid support.

24. The method of claim 20, wherein the test peptide has a sequence of 12 amino acids including a consecutive stretch of 5 or more hydrophobic amino acid residues.

25. The method of claim 20, wherein the microbe is a Gram negative bacteria.

26. The method of claim 25, wherein the Gram negative bacteria is Pseudomonas aeruginosa, Escherichia coli, or Salmonella enteritidis ssp Typhimurium.

27. The method of claim 20, wherein the microbe is a Gram positive bacteria.

28. The method of claim 27, wherein the bacteria is Staphylococcus aureus, Staphylococcus epidermidis, or Enterococcus faecaelis.

29. The method of claim 20, wherein the microbe is a yeast.

30. The method of claim 29, wherein the yeast is Candida albicans.

31. The method of claim 20, wherein the microbe contains a reporter system.

32. The method of claim 31, wherein the reporter system is a bacterial luciferase construct inserted into the chromosome.

33. The method of claim 32, wherein the reporter system is inserted into the fliC gene in Pseudomonas aeruginosa.

34. A pharmaceutical composition comprising a peptide of claim 1 or a polypeptide of claim 6 and a pharmaceutically acceptable carrier.

35. A method of modulating microbial activity in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the pharmaceutical composition of claim 34.

36. A method of treating a disease or disorder associated with microbial activity in a subject comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 34.