CA2432978A1 - Compositions and methods for the treatment and prevention of cardiovascular diseases and disorders, and for identifying agents therapeutic therefor - Google Patents

Compositions and methods for the treatment and prevention of cardiovascular diseases and disorders, and for identifying agents therapeutic therefor Download PDF

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CA2432978A1
CA2432978A1 CA002432978A CA2432978A CA2432978A1 CA 2432978 A1 CA2432978 A1 CA 2432978A1 CA 002432978 A CA002432978 A CA 002432978A CA 2432978 A CA2432978 A CA 2432978A CA 2432978 A1 CA2432978 A1 CA 2432978A1
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sphingolipid
enzyme
optionally substituted
agent
treating
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CA2432978C (en
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Roger A. Sabbadini
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Apollo Endosurgery Inc
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10—Transferases (2.)
    • C12N9/12—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
    • C12N9/1288—Transferases for other substituted phosphate groups (2.7.8)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10—Transferases (2.)
    • C12N9/12—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
    • C12N9/1205—Phosphotransferases with an alcohol group as acceptor (2.7.1), e.g. protein kinases
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/78—Hydrolases (3) acting on carbon to nitrogen bonds other than peptide bonds (3.5)
    • C12N9/80—Hydrolases (3) acting on carbon to nitrogen bonds other than peptide bonds (3.5) acting on amide bonds in linear amides (3.5.1)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/92—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving lipids, e.g. cholesterol, lipoproteins, or their receptors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/32—Cardiovascular disorders

Abstract

Methods and compositions are disclosed that are useful for the prevention and/or treatment of cardiovascular and cardiac diseases and disorders, or damage resulting from surgical or medical procedures that may cuase ischemic or ischemic/reperfusion damage in humans; and cardiovascular trauma. The beneficial effects of the compositions and methods are achieved through the use of pharmaceutical compositions that include agents that interfere with t he production and/or biological activities of sphingolipids and their metabolites, particularly sphingosine (SPH) and sphingosine-1-phosphate (S-1 - P). Also disclosed are methods for identifying and isolating therapeutic agents.

Claims (141)

1. A method for treating or preventing cardiovascular disease, comprising administering an agent that alters the activity or concentration of an enzyme, wherein said enzyme catalyzes a reaction that produces or degrades a sphingolipid or a sphingolipid metabolite.
2. A method of claim 1, wherein said cardiovascular disease is a cardiac disease.
3. The method of claim 2, wherein said cardiac disease is selected from the group consisting of myocardial ischemia; acute myocardial infarction (AMI);
coronary artery disease (CAD); acute coronary syndrome (ACS); cardiac cell and tissue damage that may occur during or as a consequence of pericutaneous revascularization (coronary angioplasty) with or without stenting; coronary bypass grafting (CABG) or other surgical or medical procedures or therapies that may cause ischemic or ischemic/reperfusion damage; and cardiovascular trauma.
4. A method for treating or preventing cerebrovascular disease, comprising administering an agent that alters the activity or concentration of an enzyme, wherein said enzyme catalyzes a reaction that produces or degrades a sphingolipid or a sphingolipid metabolite.
5. A method for treating or preventing undesirable post-ischemic events in an animal, comprising administering thereto an agent that alters the activity or concentration of an enzyme, wherein said enzyme catalyzes a reaction that produces or degrades a sphingolipid or a sphingolipid metabolite.
6. The method of claim 5 wherein said undesirable post-ischemic events occur in the heart.
7. The method of claim 5 wherein said undesirable post-ischemic events occur in the brain.
8. A method for treating or preventing cardiovascular disease, comprising administering an agent that alters the activity or concentration of an enzyme, wherein said enzyme catalyzes a reaction that produces or degrades sphingomyelin.
9. The method of claim 8, wherein said agent inhibits an enzyme that produces sphingomyelin.
10. The method of claim 9, wherein said enzyme is SM synthase.
11. The method of claim 8, wherein said agent stimulates an enzyme that degrades sphingomyelin.
12. The method of claim 11, wherein said enzyme is SM deacylase or SMase.
13. A method for treating or preventing cardiovascular disease, comprising administering an agent that alters the activity or concentration of an enzyme, wherein said enzyme catalyzes a reaction that produces or degrades a sphingolipid or a sphingolipid metabolite other than sphingomyelin.
14. The method of claim 1, wherein said sphingolipid is sphingosine.
15. The method of claim 14, wherein said agent inhibits an enzyme that produces sphingosine.
16. The method of claim 15, wherein said enzyme is ceramidase or S-1-P
phosphatase.
17. The method of claim 14, wherein said agent stimulates an enzyme that degrades sphingosine.
18. The method of claim 17, wherein said enzyme is SPH kinase or ceramide synthase.
19. The method of claim 1, wherein said sphingolipid is S-1-P.
20. The method of claim 19, wherein said agent inhibits an enzyme that produces S-1-P.
21. The method of claim 20, wherein said enzyme is SPH kinase.
22. The method of claim 14, wherein said agent stimulates an enzyme that degrades S-1-P.
23. The method of claim 22, wherein said enzyme is S-1-P phosphatase or S-1-P
lyase.
24. The method of claim 1, wherein said sphingolipid is ceramide.
25. The method of claim 24, wherein said agent inhibits an enzyme that produces ceramide.
26. The method of claim 25, wherein said enzyme is desaturase, SMase, cerebrosidase, or Cer-1-P phosphatase.
27. The method of claim 24, wherein said agent stimulates an enzyme that degrades ceramide.
28. The method of claim 27, wherein said enzyme is SM synthase, Cer kinase, ceramidase, or an enzyme that produces galactosylceramide.
29. The method of claim 1, wherein said sphingolipid is SPC.
30. The method of claim 29, wherein said agent inhibits an enzyme that produces SPC.
31. The method of claim 30, wherein said enzyme is SM deacylase.
32. The method of claim 1, wherein said enzyme catalyzes a reaction that produces or degrades a sphingolipid metabolite.
33. The method of claim 32, wherein said sphingolipid metabolite is 3-ketosphinganine.
34. The method of claim 33, wherein said agent inhibits an enzyme that produces 3-ketosphinganine.
35. The method of claim 34, wherein said enzyme is SPT.
36. The method of claim 32, wherein said sphingolipid metabolite is sphinganine.
37. The method of claim 36, wherein said agent inhibits an enzyme that produces sphinganine.
38. The method of claim 37, wherein said enzyme is NADPH-dependent reductase.
39. The method of claim 32, wherein said sphingolipid metabolite is dihydroceramide.
40. The method of claim 39, wherein said agent inhibits an enzyme that produces dihydroceramide.
41. The method of claim 40, wherein said enzyme is ceramide synthase.
42. A method for treating or preventing cerberovascular disease, comprising administering an agent that alters the activity or concentration of an enzyme, wherein said enzyme catalyzes a reaction that produces or degrades a sphingolipid or a sphingolipid metabolite other than sphingomyelin.
43. A method for treating or preventing cardiovascular disease, comprising administering an agent that binds a sphingolipid or a sphingolipid metabolite.
44. The method of claim 43 wherein said agent is an antibody or antibody derivative.
45. The method of claim 44 wherein said antibody is monoclonal, monospecific or polyclonal.
46. The method of claim 45 wherein said antibody is a single-chain antibody.
47. The method of claim 42 wherein said agent is a non-catalytic derivative of an enzyme involved in the sphingolipid metabolic pathways.
48. The method of claim 42 wherein said agent is a soluble fragment of a receptor that binds a sphingolipid.
49. The method of claim 48 wherein said sphingolipid is S-1-P.
50. The method of claim 48 wherein said receptor is selected from the group consisting of Edg-1, Edg-3, Edg-5, Edg-6, Edg-8, the Mil receptor, AXOR29, NRG1, SCaMPER and homologs and isoforms thereof.
51. A method for treating or preventing cerebrovascular disease, comprising administering an agent that binds a sphingolipid or a sphingolipid metabolite.
52. A method for treating or preventing cardiovascular disease, comprising administering a nucleic acid selected from the group consisting of an oligonucleotide having a sequence that is antisense to a nucleotide sequence found within an mRNA that encodes an enzyme that catalyzes a reaction that results in the production of a sphingolipid; a gene therapy construct comprising a nucleic acid having a sequence that is antisense to a nucleotide sequence found within an mRNA that encodes an enzyme that catalyzes a reaction that results in the production of a sphingolipid; a gene therapy construct comprising a nucleic acid having a nucleotide sequence that encodes a dominant negative mutant of an enzyme that catalyzes a reaction that results in the production of a sphingolipid; and a gene therapy construct comprising a nucleic acid having a nucleotide sequence that encodes an enzyme that catalyzes a reaction that results in the degradation of a sphingolipid or a sphingolipid metabolite.
53. A method for treating or preventing cardiovascular disease, comprising administering a nucleic acid selected from the group consisting of an oligonucleotide having a sequence that is antisense to a nucleotide sequence found within an mRNA that encodes an enzyme that catalyzes a reaction that results in the production of a sphingolipid; a gene therapy construct comprising a nucleic acid having a sequence that is antisense to a nucleotide sequence found within an mRNA that encodes an enzyme that catalyzes a reaction that results in the production of a sphingolipid; a gene therapy construct comprising a nucleic acid having a nucleotide sequence that encodes a dominant negative mutant of an enzyme that catalyzes a reaction that results in the production of a sphingolipid; and a gene therapy construct comprising a nucleic acid having a nucleotide sequence that encodes an enzyme that catalyzes a reaction that results in the degradation of a sphingolipid or a sphingolipid metabolite.
54. A method for treating or preventing cerebrovascular disease, comprising administering a nucleic acid selected from the group consisting of an oligonucleotide having a sequence that is antisense to a nucleotide sequence found within an mRNA that encodes an enzyme that catalyzes a reaction that results in the production of a sphingolipid; a gene therapy construct comprising a nucleic acid having a sequence that is antisense to a nucleotide sequence found within an mRNA that encodes an enzyme that catalyzes a reaction that results in the production of a sphingolipid; a gene therapy construct comprising a nucleic acid having a nucleotide sequence that encodes a dominant negative mutant of an enzyme that catalyzes a reaction that results in the production of a sphingolipid; and a gene therapy construct comprising a nucleic acid having a nucleotide sequence that encodes an enzyme that catalyzes a reaction that results in the degradation of a sphingolipid or a sphingolipid metabolite.
55. A method for treating or preventing cardiovascular disease comprising administering a protein or a polypeptide derivative thereof that is a dominant negative mutant of a receptor that binds a sphingolipid or a sphingolipid metabolite.
56. The method of claim 55 wherein said sphingolipid is S-1-P, sphingosine or ceramide.
57. A method for treating or preventing cerebrovascular disease comprising administering a protein or a polypeptide derivative thereof that is a dominant negative mutant of a receptor that binds a sphingolipid or a sphingolipid metabolite.
58. A method for treating or preventing cerebrovascular disease comprising administering a protein or a polypeptide derivative thereof that is a dominant negative mutant of a receptor that binds a sphingolipid or a sphingolipid metabolite.
59. A method for treating or preventing cardiovascular disease comprising administering an agent that modulates the sphingomyelin signaling pathway.
60. A method for treating or preventing cerebrovascular disease comprising administering an agent that modulates the sphingomyelin signaling pathway.
61. A pharmaceutical composition comprising compound that binds a sphingolipid, wherein said compound is not antibody or antibody derivative.
62. The pharmaceutical composition of claim 61, wherein said compound is a polypeptide.
63. The pharmaceutical composition of claim 62 wherein said polypeptide is a soluble receptor fragment.
64. The pharmaceutical composition of claim 62, wherein said compound is a nucleic acid.
65. The pharmaceutical composition of claim 64, wherein said nucleic acid is an aptamer.
66. The pharmaceutical composition of claim 61, wherein said compound is a small molecule.
67. The pharmaceutical composition of Claim 61 comprising a compound that binds a sphingolipid.
68. A pharmaceutical composition comprising a nucleic acid selected from the group consisting of an oligonucleotide having a sequence that is antisense to a nucleotide sequence found within an mRNA that encodes an enzyme that catalyzes a reaction that results in the production of a sphingolipid; a gene therapy construct comprising a nucleic acid having a sequence that is antisense to a nucleotide sequence found within an mRNA that encodes an enzyme that catalyzes a reaction that results in the production of a sphingolipid; a gene therapy construct comprising a nucleic acid having a nucleotide sequence that encodes a dominant negative mutant of an enzyme that catalyzes a reaction that results in the production of a sphingolipid;
and a gene therapy construct comprising a nucleic acid having a nucleotide sequence that encodes an enzyme that catalyzes a reaction that results in the degradation of a sphingolipid or a sphingolipid metabolite.
69. A pharmaceutical composition comprising an inhibitor of a SMase.
70. The pharmaceutical composition of claim 69, wherein said SMase is a neutral SMase.
71. The pharmaceutical composition of claim 69, wherein said pharmaceutical composition is formulated for rapid cardiac delivery.
72. A method of treating or preventing a cardiovascular disease, comprising administering the pharmaceutical composition of claim 61 to an animal in need thereof.
73. The method of claim 72, wherein said cardiovascular disease is a heart disease.
74. The method of claim 73, wherein said heart disease is selected from the group consisting of heart failure, cardiac ischemia and cardiac hypoxia.
75. The method of claim 74, wherein said heart failure is selected from the group consisting of acute myocardial infarction, myocarditis, a cardiomyopathy, congestive heart failure and idopathic heart failure.
76. A method of treating or preventing a cerebrovascular disease, comprising administering the pharmaceutical composition of claim 61 to an animal in need thereof.
77. The method of claim 76, wherein said cerebrovascular disease is selected from the group consisting of cerebral ischemia and cerebral hypoxia.
78. A medical device comprising the pharmaceutical composition of claim 61.
79. A kit comprising the medical device of claim 78, wherein said kit is designed to be used for the administration of said pharmaceutical composition in emergency situations.
80. A method of treating or preventing a cardiovascular disease using the kit of claim 69.
81. A kit comprising the medical device of claim 78, wherein said kit is designed to be used for routine administration of said pharmaceutical composition.
82. A method of treating or preventing a cardiovascular disease using the kit of claim 79.
83. A method of treating or preventing a cerebrovascular disease using the kit of claim 79.
84. A method for treating or preventing cardiovascular disease, comprising administering an agent that binds a receptor of a sphingolipid.
85. The method of claim 84 wherein said receptor is selected from the group consisting of Edg-1, Edg-3, Edg-5, Edg-6, Edg-8, the Mil receptor, AXOR29, NRG1, SCaMPER and homologs and isoforms thereof.
86. A pharmaceutical composition comprising an agent that binds a receptor of a sphingolipid.
87. A method for treating or preventing cerebrovascular disease, comprising administering an agent that binds a receptor of a sphingolipid.
88. A method of screening for an agent for treating or preventing cardiovascular disease, comprising screening a library of compounds for agents that inhibit an enzyme that produces a sphingolipid or a sphingolipid metabolite.
89. The method of claim 88, wherein said sphingolipid is sphingomyelin.
90. The method of claim 89, wherein said enzyme is SM synthase.
91. The method of claim 88, wherein said sphingolipid is S-1-P.
92. The method of claim 91, wherein said enzyme is SPH kinase.
93. The method of claim 88, wherein said sphingolipid is SPH.
94. The method of claim 93, wherein said enzyme is ceramidase or S-1-P
phosphatase.
95. The method of claim 88, wherein said sphingolipid is ceramide.
96. The method of claim 95, wherein said enzyme is desaturase, ceramide synthase, Cer-1-P phosphatase, cerebrosidase or SMase.
97. The method of claim 90, wherein said library of compounds is a library of aminoglyocosides.
98. A method of screening for an agent for treating or preventing cerebrovascular disease, comprising screening a library of compounds for agents that inhibit an enzyme that produces a sphingolipid or a sphingolipid metabolite.
99. A method of screening for an agent for treating or preventing cardiovascular disease, comprising screening a library of compounds for agents that stimulate an enzyme that degrades a sphingolipid or a sphingolipid metabolite.
100. The method of claim 99, wherein said sphingolipid is sphingomyelin.
101. The method of claim 100, wherein said enzyme is SM deacylase or SMase.
102. The method of claim 99, wherein said sphingolipid is S-1-P.
103. The method of claim 102, wherein said enzyme is S-1-P phosphatase or S-1-P lyase.
104. The method of claim 98, wherein said sphingolipid is sphingosine.
105. The method of claim 104, wherein said enzyme is SPH kinase or ceramide synthase.
106. The method of claim 98, wherein said sphingolipid is ceramide.
107. The method of claim 106, wherein said enzyme is SM synthase, Cer kinase, ceramidase, or an enzyme that produces galactosylceramide.
108. The method of claim11, wherein said agent is an aminoglycoside.
109. The method claim 108, wherein said aminoglycoside is a gentamicin.
110. The method claim 109, wherein said agent that inhibits SMase has the structure wherein:
each of R1-R13 is independently hydrogen, alkyl, optionally substituted alkyl, alkenyl, optionally substituted alkenyl, alkynyl, optionally substituted alkynyl, aryl, optionally substituted aryl, cycloalkyl, optionally substituted cycloalkyl, alkoxy, optionally substituted alkoxy, heterocyclic, optionally substituted heterocyclic, heteroaryl, optionally substituted heteroaryl, hydroxyl, halogen, nitro, carboxyl, thioalkyl, amino, alkylamino, arylamino, amido, ammonium, alkylammonium, sulfonyl, aminosulfonyl, alkylsulfonyl, alkoxycarbonyl, acetyl, or acyl.
111. The method claim 110, wherein:

each of R1-R13 is independently hydrogen, alkyl, optionally substituted alkyl, alkenyl, optionally substituted alkenyl, alkynyl, optionally substituted alkynyl, alkoxy, optionally substituted alkoxy, aryl, optionally substituted aryl, cycloalkyl, optionally substituted cycloalkyl, heterocyclic, optionally substituted heterocyclic, heteroaryl, optionally substituted heteroaryl, hydroxyl, halogen, nitro, carboxyl, thioalkyl, amino, alkylamino, arylamino, amido, ammonium, alkylammonium, sulfonyl, aminosulfonyl, alkylsulfonyl, alkoxycarbonyl, acetyl, or acyl, with the proviso that when R6 = H, R7 = H, R8 = CH3, R9 = OH, R10 = CH3, R11 = H, R12 = OH, and R13 = OH, if R1 = NH2, R2 = H, R3 = H, and R4 =
CH3, then R5 is not NH2 or NHCH3; and if R1 = OH, R2 = OH, R3 = OH, and R4 is H, then R5 is not NH2.
112. The method claim 110, wherein R1 = NH2; R2 = H; R3 = H; R4 = CH3; R5 = NH2 or NHCH3,; R6 = H; R7 = H; R8 = CH3; R9 = OH; R10 = CH3; R11 = H; R12 = OH, and R13 = OH.
113. The method claim 110, wherein R1 = OH, R2 = OH; R3 = OH; R4 = H; R5 = NH2; R6 = H; R7 = H; R8 = CH3; R9 = OH; R10 = CH3; R11 = H; R12 =
OH; and R13 = OH.
114. A method of screening for an agent for treating or preventing cardiovascular or cerbrovascular disease, comprising screening a library of compounds for agents that inhibit or stimulate an enzyme that produces a sphingolipid or a sphingolipid metabolite.
115. The method of claim 114, wherein said sphingolipid or a sphingolipid metabolite is selected from the group consisting of sphingomyelin, sphingosine, S-1-P, ceramide, SPC, 3-ketosphinganine, galactosylceramide and dihydroceramide.
116. The method of claim 114, wherein said enzyme is selected from the group consisting of SM synthase, SM deacylase, SMase, ceramidase, S-1-P
phosphatase, SPH kinase, Cer synthase, S-1-P lyase, cerebrosidase, Cer-1-P
phosphatase, Cer kinase, SM deacylase, SPT, NADPH-dependent reductase.
117. The method of claim 114, wherein said sphingolipid is ceramide, sphingosine or S-1-P.
118. The method of claim 114, wherein said library of compounds is a library of lipids.
119. The method claim 114, wherein said enzyme is SMase.
120. The method of claim 119, wherein said library of compounds is a library of aminoglyocosides.
121. The method claim 120, wherein members of said library of aminoglycosides have the structure wherein:

each of R1-R13 is independently hydrogen, alkyl, optionally substituted alkyl, alkenyl, optionally substituted alkenyl, alkynyl, optionally substituted alkynyl, aryl, optionally substituted aryl, cycloalkyl, optionally substituted cycloalkyl, alkoxy, optionally substituted alkoxy, heterocyclic, optionally substituted heterocyclic, heteroaryl, optionally substituted heteroaryl, hydroxyl, halogen, nitro, carboxyl, thioalkyl, amino, alkylamino, arylamino, amido, ammonium, alkylammonium, sulfonyl, aminosulfonyl, alkylsulfonyl, alkoxycarbonyl, acetyl, or acyl.
122. The method claim 121, wherein each of R1-R13 is independently hydrogen, alkyl, optionally substituted alkyl, alkenyl, optionally substituted alkenyl, alkynyl, optionally substituted alkynyl, alkoxy, optionally substituted alkoxy, aryl, optionally substituted aryl, cycloalkyl, optionally substituted cycloalkyl, heterocyclic, optionally substituted heterocyclic, heteroaryl, optionally substituted heteroaryl, hydroxyl, halogen, nitro, carboxyl, thioalkyl, amino, alkylamino, arylamino, amido, ammonium, alkylammonium, sulfonyl, aminosulfonyl, alkylsulfonyl, alkoxycarbonyl, acetyl, or acyl, with the proviso that when R6 = H, R7 = H, R8 = CH3, R9 = OH, R10 = CH3, R11 = H, R12 = OH, and R13 = OH, if R1 = NH2, R2 = H, R3 = H, and R4 = CH3, then R5 is not NH2 or NHCH3, and if R1 = OH, R2 = OH, R3 = OH, and R4 is H, then R5 is not NH2.
123. The method claim 121, wherein R1 = NH2; R2 = H; R3 = H; R4 = CH3; R5 = NH2 or NHCH3; R6 = H; R7 = H; R8 = CH3; R9 = OH; R10 = CH3; R11 = H; R12 = OH, and R13 = OH.
124. The method claim 121, wherein R1 = OH; R2 = OH; R3 = OH; R4 = H; R5 = NH2; R6 = H; R7 = H; R8 = CH3; R9 = OH; R10 = CH3; R11 = H; R12 =
OH; and R13 = OH.
125. The method of 114, wherein said library of compounds is a library of lipids.
126. The method of 125, wherein said library of compounds is a library of sphingolipids.
127. A nucleic acid having the nucleotide sequence SEQ ID NO:3.
128. A polypeptide encoded by the nucleic acid of claim 127.
129. A nucleic acid having the nucleotide sequence SEQ ID NO:4.
130. A polypeptide encoded by the nucleic acid of claim 129.
131. A nucleic acid having the nucleotide sequence SEQ ID NO:7.
132. A polypeptide encoded by the nucleic acid of claim 130.
133. An expression construct comprising a nucleic acid having a sequence selected from the group consisting of SEQ ID NOS: 3, 4, and 7.
134. A host cell comprising the expression vector of claim 133.
135. A method of producing a polypeptide, comprising culturing the host cell of claim 134.
136. An expression construct comprising a portion of a nucleic acid having a portion of sequence selected from the group consisting of SEQ ID NOS: 3, 4, and 7, wherein said portion of said sequence lacks nucleotide sequences that encode a transmembrane domain of a polypeptide encoded thereby.
137. A host cell comprising the expression vector of claim 136.
138. A method of producing a soluble receptor fragment, comprising culturing the host cell of claim 137.
139. A formulation comprising an agent which will, when provided to an animal in need thereof, alter the activity or concentration of an enzyme that produces or degrades a sphingolipid or a sphingolipid metabolite to a degree necessary to achieve a therapeutic effect.
140. The formulation of claim 139, wherein said agent is an aminoglycoside.
141. The formulation of claim 139, wherein said aminoglycoside is a gentamicin.
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