US20040039167A1 - Maurotoxin, pi1 and hstx1 derivatives - Google Patents
Maurotoxin, pi1 and hstx1 derivatives Download PDFInfo
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- US20040039167A1 US20040039167A1 US10/363,622 US36362203A US2004039167A1 US 20040039167 A1 US20040039167 A1 US 20040039167A1 US 36362203 A US36362203 A US 36362203A US 2004039167 A1 US2004039167 A1 US 2004039167A1
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- maurotoxin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/43504—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates
- C07K14/43513—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates from arachnidae
- C07K14/43522—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates from arachnidae from scorpions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the invention relates to derivatives of maurotoxin and of particular toxins belonging to the same structural class of K + channel-acting short-chain scorpion toxins (less than 40 amino acid residues) that are cross-linked by four disulfide bridges, such as Pi1 and HsTx1.
- disulfide bridges such as Pi1 and HsTx1.
- toxin derivatives contemplated by the invention are truncated, modified, and mutated toxins (with either natural or non-natural amino acid residues, or non-natural peptide bonds or linkages) with four, or less than four, disulfide bridges. Mimetics of these compounds are also included.
- the invention also relates to the use of all these derivatives and mimetics for the treatment of neurological disorders, including immunological neurological disorders, associated with their action on modulation or blockade of specific K + channels, Ca 2+ -activated and/or voltage-gated subtypes, and to pharmaceutical compositions containing them.
- Maurotoxin a toxin from the venom of the Tunisian chactidae scorpion Scorpio maurus palmatus, is a 34-mer peptide cross-linked by four disulfide bridges.
- the sequence of amino acid residues in MTX is VSCTGSKDCYAPCRKQTGCPNAKClNKSCKCYGC-NH 2 [SEQ. ID NO. 1].
- MTX belongs to a distinct family of short-chain scorpion toxins with less than 40 residues, that are active onto several potassium channel subtypes (Kv and KCa channels).
- This family can be distinguished by the presence of an additional disulfide bridge (four instead of the three commonly present in such toxins).
- This structural class also includes Pi1 [SEQ. ID NO. 2] and HsTx1 [SEQ. ID NO. 3] from the venoms of the scorpions Pandinus imperator and Heteroticians spinnifer , respectively.
- These toxins share from 53 to 68% sequence identity with MTX but display different pharmacological selectivities. For instance, MTX and Pi1 are both active on some Ca 2+ -activated K + channels, e.g. apamin-sensitive SK channels, whereas HsTx1 is reportedly inactive on these channel types.
- MTX was found to be active on rat Kv1.3 channels contrary to synthetic Pi1.
- MTX structurally differs from Pi1 and HsTx1, but also from other “classical” three disulfide-bridged scorpion toxins, by its unique disulfide bridge pattern.
- the half-cystine pairings are of the type C1-C4, C2-C5 and C3-C6 (e.g. charybdotoxin, PO 5 , agitoxin 2, leiurotoxin 1).
- the invention provides MTX, Pi1 and HsTx1 derivatives, in which specific residue replacements, or a reorganization of half-cystine pairings has taken place, resulting in a novel, highly potent and more selective pharmacological profile.
- the substitution of the MTX half-cystine residues results in a two disulfide-bridged MTX analog, i.e. VSCTGSKDAbuYAPCRKQTGAbuPNAKClNKSAbuKCYGAbu-NH 2 , with novel, non-native arrangement of the half-cystine pairings (Cys3-Cys24 and Cys13-Cys31).
- MTX and Pil derivatives such as [Abu9,19,29,34]-MTX or [Q15]-MTX are neither lethal nor toxic when injected intracerebroventricularly in these mice at active concentrations (up to 1.25 mg/kg in the case of [Abu9, 19, 29, 34]-MTX).
- the MTX derivatives, as well as the MTX structurally homologous Pi1 or HsTx1 derivatives, of the invention are thus of potential therapeutic value for treating mammalian (including human) pathologies that are associated with a dysfunctioning of Ca 2+ -activated and/or voltage-gated Kv channel subtypes.
- pathologies include immune and/or neurological diseases like multiple sclerosis, Parkinson's and Alzheimer's diseases, both thought to be associated with a dysfunctioning of Ca 2+ -activated and/or voltage-gated K + channel subtype(s).
- the axonal impulse propagation ensures a continued transmission of nervous signals to remote targets. In a number of neuropathies, the nervous conduction is either slowed down or locked.
- K + -channel blockers including Ca 2+ -activated K + channel-acting and/or Kv-acting MTX/Pi1/HsTx1-derived peptides such as [Q15]-MTX, Pi1 amidated at C-terminus, [Abu9,19,29,34]-MIX, are of potential therapeutic value as symptomatic therapy of multiple sclerosis and related neuropathies, as well as for use as selective immuno-suppressant drugs by their blocking action on Ca 2+ -activated and/or Kv channels. Further, it can be speculated that such peptide blockers, in the CNS, could enhance transmitter release in pathways affected by progressive neurodegenerative diseases such as Alzheimer's disease.
Abstract
Description
- The invention relates to derivatives of maurotoxin and of particular toxins belonging to the same structural class of K+ channel-acting short-chain scorpion toxins (less than 40 amino acid residues) that are cross-linked by four disulfide bridges, such as Pi1 and HsTx1. Among the toxin derivatives contemplated by the invention are truncated, modified, and mutated toxins (with either natural or non-natural amino acid residues, or non-natural peptide bonds or linkages) with four, or less than four, disulfide bridges. Mimetics of these compounds are also included. The invention also relates to the use of all these derivatives and mimetics for the treatment of neurological disorders, including immunological neurological disorders, associated with their action on modulation or blockade of specific K+ channels, Ca2+-activated and/or voltage-gated subtypes, and to pharmaceutical compositions containing them.
- Maurotoxin (MTX), a toxin from the venom of theTunisian chactidae scorpion Scorpio maurus palmatus, is a 34-mer peptide cross-linked by four disulfide bridges. The sequence of amino acid residues in MTX is VSCTGSKDCYAPCRKQTGCPNAKClNKSCKCYGC-NH2 [SEQ. ID NO. 1]. MTX belongs to a distinct family of short-chain scorpion toxins with less than 40 residues, that are active onto several potassium channel subtypes (Kv and KCa channels). Contrary to most short-chain K+ channel-acting scorpion toxins, this family can be distinguished by the presence of an additional disulfide bridge (four instead of the three commonly present in such toxins). This structural class also includes Pi1 [SEQ. ID NO. 2] and HsTx1 [SEQ. ID NO. 3] from the venoms of the scorpions Pandinus imperator and Heterometrus spinnifer, respectively. These toxins share from 53 to 68% sequence identity with MTX but display different pharmacological selectivities. For instance, MTX and Pi1 are both active on some Ca2+-activated K+ channels, e.g. apamin-sensitive SK channels, whereas HsTx1 is reportedly inactive on these channel types. Also, MTX was found to be active on rat Kv1.3 channels contrary to synthetic Pi1. Interestingly, MTX structurally differs from Pi1 and HsTx1, but also from other “classical” three disulfide-bridged scorpion toxins, by its unique disulfide bridge pattern. In three disulfide-bridged toxins, the half-cystine pairings are of the type C1-C4, C2-C5 and C3-C6 (e.g. charybdotoxin, PO5, agitoxin 2, leiurotoxin 1). In short-chain four disulfide-bridged toxins, this pattern is altered by the insertion of two additional half-cystines within the amino acid sequence, one located after C3 and the other after C6. As a result, two novel patterns of the disulfide bridges are experimentally found depending on the toxin: (i) a pattern of the type C1-C5, C2-C6, C3-C7 and C4-C8 in both Pi1 and HsTx1 (which corresponds to an organization similar to that observed in three disulfide-bridged toxins), and (ii) an uncommon pattern of the type C1-C5, C2-C6, C3-C4 and C7-C8 in MTX. These two patterns possess in common the first two disulfide bridges but are differing by the two remaining disulfides. Though differences in pharmacological properties between short-chain four disulfide-bridged toxins obviously rely on their distinct amino acid sequences, it is also possible that changes in half-cystine pairings may contribute to either dramatic or discrete conformational alterations and repositioning of key residues that are involved in toxin selectivity. At the pharmacological level, MTX displays an uncommon enlarged specificity, being active—in the picomolar or nanomolar concentration range—on both Ca2+-activated K+ channels, e.g. small conductance apamin-sensitive Ca2+-activated K+ (SK) channels, and several voltage-gated (Kv) K+ channel subtypes, including Kv1.2
- In J. Biol. Chem., Vol. 275, No. 18, pp 13605-13612, 2000, Fajloun et al have described an MTX derivative with three instead of four disulfide bridges, formed by substituting α-aminobutyrate (Abu) residues for the Cys residues located at positions 19 and 34 (corresponding by numbers to positions C4 and C8). This derivative adopts the α/β scaffold with now conventional half-cystine pairings connecting C1-C5, C2-C6 and C3-C7 but remains lethal in mice by intracerebroventricular injection (LD50: 0.25 μg/mouse).
- The invention provides MTX, Pi1 and HsTx1 derivatives, in which specific residue replacements, or a reorganization of half-cystine pairings has taken place, resulting in a novel, highly potent and more selective pharmacological profile.
- In one preferred derivative, the substitution of the MTX half-cystine residues (by amino butyrate derivatives) located at positions 9, 19, 29, and 34 (corresponding by numbers to C2, C4, C6, and C8) results in a two disulfide-bridged MTX analog, i.e. VSCTGSKDAbuYAPCRKQTGAbuPNAKClNKSAbuKCYGAbu-NH2, with novel, non-native arrangement of the half-cystine pairings (Cys3-Cys24 and Cys13-Cys31). Pharmacological assays of this structural analog, [Abu9,19,29,34]-MTX, reveal that the blocking activity is potent (IC50=42 nM) and highly selective for mammalian voltage-gated Kv1.2 channel subtype, although it remains active on Ca2+-activated K+ channels.
- An alternative approach to replacement of Cys residues with Abu is the replacement of one or two amino acid residues in natural MTX with other residues which prevent the folding of the molecule in such a way that the unconventional C 1-C5, C2-C6, C3-C7 and C4-C8 disulfide bridge arrangement can occur. For instance, if neither of the residues at positions 32 and 33 is a Gly or Pro residue, the folding is altered in such a way that the MTX derivative adopts the conventional C1-C5, C2-C6, C3-C7 and C4-C8 of Pi1 and HsTx1. In particular, replacement of the Gly residue at position 33 by an Ala residue substitution, forming [A33]-MTX [SEQ. ID NO. 4], is effective. Substitution of Arg14 and/or Lys15 by Gln to give [Q14]-MTX [SEQ. ID NO. 5], [Q15]-MTX [SEQ. ID NO. 6] or [Q14,Q15]-MTX [SEQ. ID NO. 7] also induces half-cystine pairings between Cys3-Cys24, Cys9-Cys29, Cys13-Cys31 and Cys19-Cys34. [Q15]-MTX in particular was 1,000 times more potent than [Abu9,19,29,34]-MTX on mammalian voltage-gated Kv1.2 (IC50=47 pM).
- Contrary to natural MTX and Pil which are lethal in C57/BL6 mice (LD50=4 mcg/kg of MTX or 10 mcg/kg of Pil), MTX and Pil derivatives such as [Abu9,19,29,34]-MTX or [Q15]-MTX are neither lethal nor toxic when injected intracerebroventricularly in these mice at active concentrations (up to 1.25 mg/kg in the case of [Abu9, 19, 29, 34]-MTX). The MTX derivatives, as well as the MTX structurally homologous Pi1 or HsTx1 derivatives, of the invention are thus of potential therapeutic value for treating mammalian (including human) pathologies that are associated with a dysfunctioning of Ca2+-activated and/or voltage-gated Kv channel subtypes. Such pathologies include immune and/or neurological diseases like multiple sclerosis, Parkinson's and Alzheimer's diseases, both thought to be associated with a dysfunctioning of Ca2+-activated and/or voltage-gated K+ channel subtype(s). The axonal impulse propagation ensures a continued transmission of nervous signals to remote targets. In a number of neuropathies, the nervous conduction is either slowed down or locked. This could be linked to alteration or functional changes of myelinated fibres (demyelinisation or alteration of the membrane properties at the Ranvier nodes). Among these neuropathies are multiple sclerosis (central nervous system; CNS) and Guillain-Barré syndrome (peripheral nervous system). It is now well-admitted that alteration of the axonal function is related to the presence of voltage-gated (Kv) K+ channels (there is a widespread distribution of Kv1.1 and Kv1.2 channel subtypes in nerve terminals throughout the brain, whereas Kv channels -independent of their subtypes- are considered to be ubiquitous, including in the peripheral nervous system), and possibly Ca2+-activated K+ channels. In the previously cited neuropathies, Ca2+-activated K+ channels and Kv channels are either abnormally exposed in demyelinated or inflammatory lesions, or over-expressed. Therefore, selective K+-channel blockers, including Ca2+-activated K+ channel-acting and/or Kv-acting MTX/Pi1/HsTx1-derived peptides such as [Q15]-MTX, Pi1 amidated at C-terminus, [Abu9,19,29,34]-MIX, are of potential therapeutic value as symptomatic therapy of multiple sclerosis and related neuropathies, as well as for use as selective immuno-suppressant drugs by their blocking action on Ca2+-activated and/or Kv channels. Further, it can be speculated that such peptide blockers, in the CNS, could enhance transmitter release in pathways affected by progressive neurodegenerative diseases such as Alzheimer's disease.
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1 7 1 34 PRT Scorpio Maurus palmatus 1 Val Ser Cys Thr Gly Ser Lys Asp Cys Tyr Ala Pro Cys Arg Lys Gln 1 5 10 15 Thr Gly Cys Pro Asn Ala Lys Cys Ile Asn Lys Ser Cys Lys Cys Tyr 20 25 30 Gly Cys 2 35 PRT Scorpio Pandinus imperator 2 Leu Val Lys Cys Arg Gly Thr Ser Asp Cys Gly Arg Pro Cys Gln Gln 1 5 10 15 Gln Thr Gly Cys Pro Asn Ser Lys Cys Ile Asn Arg Met Cys Lys Cys 20 25 30 Tyr Gly Cys 35 3 34 PRT Scorpio Heterometrus spinnifer 3 Ala Ser Cys Arg Thr Pro Lys Asp Cys Ala Asp Pro Cys Arg Lys Glu 1 5 10 15 Thr Gly Cys Pro Tyr Gly Lys Cys Met Asn Arg Lys Cys Lys Cys Asn 20 25 30 Arg Cys 4 34 PRT Artificial Sequence MTX with Ala in place of Gly at position 33 4 Val Ser Cys Thr Gly Ser Lys Asp Cys Tyr Ala Pro Cys Arg Lys Gln 1 5 10 15 Thr Gly Cys Pro Asn Ala Lys Cys Ile Asn Lys Ser Cys Lys Cys Tyr 20 25 30 Ala Cys 5 34 PRT Artificial Sequence MTX with Gln in place of Arg at position 14 5 Val Ser Cys Thr Gly Ser Lys Asp Cys Tyr Ala Pro Cys Gln Lys Gln 1 5 10 15 Thr Gly Cys Pro Asn Ala Lys Cys Ile Asn Lys Ser Cys Lys Cys Tyr 20 25 30 Gly Cys 6 34 PRT Artificial Sequence MTX with Gln in place of Lys at position 15 6 Val Ser Cys Thr Gly Ser Lys Asp Cys Tyr Ala Pro Cys Arg Gln Gln 1 5 10 15 Thr Gly Cys Pro Asn Ala Lys Cys Ile Asn Lys Ser Cys Lys Cys Tyr 20 25 30 Gly Cys 7 34 PRT Artificial Sequence MTX with Gln-Gln in place of Arg-Lys at positions 14-15 7 Val Ser Cys Thr Gly Ser Lys Asp Cys Tyr Ala Pro Cys Gln Gln Gln 1 5 10 15 Thr Gly Cys Pro Asn Ala Lys Cys Ile Asn Lys Ser Cys Lys Cys Tyr 20 25 30 Gly Cys
Claims (14)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/009,675 US7829666B2 (en) | 2000-09-04 | 2008-01-22 | Maurotoxin, PI1 and HSTX1 derivatives |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0021639A GB0021639D0 (en) | 2000-09-04 | 2000-09-04 | Maurotoxin derivatives |
GB0021639.0 | 2000-09-04 | ||
GB0024538A GB0024538D0 (en) | 2000-10-06 | 2000-10-06 | Maurotoxin pil and hstx1 derivatives |
GB0024538.1 | 2000-10-06 | ||
PCT/EP2001/010173 WO2002020596A2 (en) | 2000-09-04 | 2001-09-03 | Maurotoxin, pi1 and hstx1 derivatives |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
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US12/009,675 Continuation US7829666B2 (en) | 2000-09-04 | 2008-01-22 | Maurotoxin, PI1 and HSTX1 derivatives |
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US20040039167A1 true US20040039167A1 (en) | 2004-02-26 |
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US10/363,622 Abandoned US20040039167A1 (en) | 2000-09-04 | 2001-09-03 | Maurotoxin, pi1 and hstx1 derivatives |
US12/009,675 Expired - Fee Related US7829666B2 (en) | 2000-09-04 | 2008-01-22 | Maurotoxin, PI1 and HSTX1 derivatives |
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US12/009,675 Expired - Fee Related US7829666B2 (en) | 2000-09-04 | 2008-01-22 | Maurotoxin, PI1 and HSTX1 derivatives |
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US (2) | US20040039167A1 (en) |
EP (1) | EP1315747B1 (en) |
AT (1) | ATE321778T1 (en) |
AU (1) | AU2002212201A1 (en) |
DE (1) | DE60118418T2 (en) |
ES (1) | ES2261491T3 (en) |
WO (1) | WO2002020596A2 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090118181A1 (en) * | 2007-05-22 | 2009-05-07 | Walker Kenneth W | Compositions and methods for producing bioactive fusion proteins |
US20090281028A1 (en) * | 2006-10-25 | 2009-11-12 | Sullivan John K | OSK1 peptide analogs and pharmaceutical compositions |
US7745575B1 (en) | 2004-06-25 | 2010-06-29 | Cellpep Pharma Inc. | OsK1 derivatives |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE202013104200U1 (en) | 2013-09-13 | 2013-10-10 | Flühs Drehtechnik GmbH | Single lever cartridge |
WO2015061826A1 (en) | 2013-10-28 | 2015-05-07 | Monash University | Novel scorpion toxin analogue and method for treating autoimmune diseases |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5945329A (en) * | 1993-10-28 | 1999-08-31 | Carlsberg A/S | Customized proteases |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6113951A (en) * | 1991-10-12 | 2000-09-05 | The Regents Of The University Of California | Use of thiol redox proteins for reducing protein intramolecular disulfide bonds, for improving the quality of cereal products, dough and baked goods and for inactivating snake, bee and scorpion toxins |
EP0912726A4 (en) * | 1996-05-10 | 2001-07-18 | Phylomed Corp | Methods for oxidizing disulfide bonds using ozone |
GB9627115D0 (en) * | 1996-12-31 | 1997-02-19 | Centre Nat Rech Scient | Alpha-amino-butyrate derivatives of venoms |
-
2001
- 2001-09-03 WO PCT/EP2001/010173 patent/WO2002020596A2/en active IP Right Grant
- 2001-09-03 AU AU2002212201A patent/AU2002212201A1/en not_active Abandoned
- 2001-09-03 EP EP01980332A patent/EP1315747B1/en not_active Expired - Lifetime
- 2001-09-03 US US10/363,622 patent/US20040039167A1/en not_active Abandoned
- 2001-09-03 AT AT01980332T patent/ATE321778T1/en not_active IP Right Cessation
- 2001-09-03 ES ES01980332T patent/ES2261491T3/en not_active Expired - Lifetime
- 2001-09-03 DE DE60118418T patent/DE60118418T2/en not_active Expired - Lifetime
-
2008
- 2008-01-22 US US12/009,675 patent/US7829666B2/en not_active Expired - Fee Related
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5945329A (en) * | 1993-10-28 | 1999-08-31 | Carlsberg A/S | Customized proteases |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7745575B1 (en) | 2004-06-25 | 2010-06-29 | Cellpep Pharma Inc. | OsK1 derivatives |
US20090281028A1 (en) * | 2006-10-25 | 2009-11-12 | Sullivan John K | OSK1 peptide analogs and pharmaceutical compositions |
US20090299044A1 (en) * | 2006-10-25 | 2009-12-03 | Sullivan John K | DNA encoding chimeric toxin peptide fusion proteins and vectors and mammalian cells for recombinant expression |
US20090305399A1 (en) * | 2006-10-25 | 2009-12-10 | Sullivan John K | DNA encoding OSK1 toxin peptide analogs and vectors and cells for combinant expression |
US7803769B2 (en) | 2006-10-25 | 2010-09-28 | Amgen Inc. | OSK1 peptide analogs and pharmaceutical compositions |
US7820623B2 (en) | 2006-10-25 | 2010-10-26 | Amgen Inc. | Conjugated toxin peptide therapeutic agents |
US7825093B2 (en) | 2006-10-25 | 2010-11-02 | Amgen Inc. | Methods of using OSK1 peptide analogs |
US7834164B2 (en) | 2006-10-25 | 2010-11-16 | Amgen Inc. | DNA encoding OSK1 toxin peptide analogs and vectors and cells for combinant expression |
US7910102B2 (en) | 2006-10-25 | 2011-03-22 | Amgen Inc. | Methods of using conjugated toxin peptide therapeutic agents |
US8043829B2 (en) | 2006-10-25 | 2011-10-25 | Amgen Inc. | DNA encoding chimeric toxin peptide fusion proteins and vectors and mammalian cells for recombinant expression |
US20090118181A1 (en) * | 2007-05-22 | 2009-05-07 | Walker Kenneth W | Compositions and methods for producing bioactive fusion proteins |
US8420779B2 (en) | 2007-05-22 | 2013-04-16 | Amgen Inc. | Compositions and methods for producing bioactive fusion proteins |
Also Published As
Publication number | Publication date |
---|---|
EP1315747A2 (en) | 2003-06-04 |
WO2002020596A3 (en) | 2002-08-01 |
AU2002212201A1 (en) | 2002-03-22 |
US20090062198A1 (en) | 2009-03-05 |
DE60118418D1 (en) | 2006-05-18 |
ES2261491T3 (en) | 2006-11-16 |
WO2002020596A2 (en) | 2002-03-14 |
ATE321778T1 (en) | 2006-04-15 |
DE60118418T2 (en) | 2007-01-11 |
EP1315747B1 (en) | 2006-03-29 |
US7829666B2 (en) | 2010-11-09 |
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