Method of treating endothelial dysfunction comprising administration of a thrombin peptide derivative
View Patent ↗Endothelial dysfunction (ED) is associated with a number of diseases and disorders. Agonists of the non-proteolytically activated thrombin receptor can be used in methods to treat ED or ED-related diseases and disorders.
1. A method of treating hypertension in a subject comprising administering to the subject a therapeutically effective amount of a 12 to 23 amino acid thrombin peptide derivative comprising a serine esterase conserved sequence and a thrombin binding domain having the sequence Arg-Gly-Asp-Ala (SEQ ID NO: 16).
2. The method of claim 1 , wherein the thrombin peptide derivative comprises an N-terminus which is unsubstituted and a C-terminus which is unsubstituted or a C-terminal amide represented by —C(O)NH 2 and the thrombin peptide derivative comprises a polypeptide having the amino sequence of Arg-Gly-Asp-Ala-Cys-X 1 -Gly-Asp-Ser-Gly-Gly-Pro-X 2 -Val (SEQ ID NO:1), wherein X 1 is Glu or Gln and X 2 is Phe, Met, Leu, His or Val.
3. The method of claim 1 , wherein the thrombin peptide derivative comprises the amino acid sequence of Ala-Gly-Tyr-Lys-Pro-Asp-Glu-Gly-Lys-Arg-Gly-Asp-Ala-Cys-X 1 -Gly-Asp-Ser-Gly-Gly-Pro-X 2 -Val (SEQ ID NO:2), or a fragment thereof, comprising amino acids 10-18 of SEQ ID NO: 2, wherein X 1 is Glu or Gln and X 2 is Phe, Met, Leu, His or Val and the thrombin peptide derivative comprises an N-terminus which is unsubstituted and a C-terminus which is unsubstituted or a C-terminal amide represented by —C(O)NH 2 .
4. The method of claim 2 , wherein the thrombin peptide derivative is the polypeptide H-Ala-Gly-Tyr-Lys-Pro-Asp-Glu-Gly-Lys-Arg-Gly-Asp-Ala-Cys-Glu-Gly-Asp-Ser-Gly-Gly-Pro-Phe-Val-NH 2 (SEQ ID NO:3).
5. A method of treating hypertension in a subject comprising administering to the subject a peptide dimer comprising two 12 to 23 amino acid thrombin peptide derivatives which, independently, comprise a serine esterase conserved sequence, and a thrombin binding domain having the sequence Arg-Gly-Asp-Ala (SEQ ID NO: 16); and wherein the dimer is essentially free of monomer.
6. The method of claim 5 , wherein the thrombin peptide derivatives each comprise an N-terminus which is unsubstituted; and a C-terminus which is unsubstituted or a C-terminal amide represented by —C(O)NH 2 .
7. The method of claim 5 , wherein the thrombin peptide derivatives each comprise the amino acid sequence Ala-Gly-Tyr-Lys-Pro-Asp-Glu-Gly-Lys-Arg-Gly-Asp-Ala-Cys-X 1 -Gly-Asp-Ser-Gly-Gly-Pro-X 2 -Val (SEQ ID NO:2), wherein X 1 is Glu or Gln and X 2 is Phe, Met, Leu, His or Val, or a fragment thereof, comprising amino acids 10-18 of SEQ ID NO:2, the thrombin peptide derivatives each comprise an N-terminus which is unsubstituted, and a C-terminus which is unsubstituted or a C-terminal amide represented by —C(O)NH 2 the dimer is essentially free of monomer; the thrombin peptide derivatives are the same, and the thrombin peptide derivatives are covalently linked through a disulfide bond.
8. The method of claim 5 , wherein the thrombin peptide derivatives each comprise the amino acid sequence Ala-Gly-Tyr-Lys-Pro-Asp-Glu-Gly-Lys-Arg-Gly-Asp-Ala-Cys-X 1 -Gly-Asp-Ser-Gly-Gly-Pro-X 2 -Val (SEQ ID NO:2), wherein X 1 is Glu or Gln and X 2 is Phe, Met, Leu, His or Val, the thrombin peptide derivatives each comprise an N-terminus which is unsubstituted; and a C-terminus which is unsubstituted or a C-terminal amide represented by —C(O)NH 2 , the dimer is essentially free of monomer; the thrombin peptide derivatives are the same, and the thrombin peptide derivatives are covalently linked through a disulfide bond.
9. The method of claim 8 , wherein X 1 is Glu and X 2 is Phe.
10. The method of claim 5 , wherein the peptide dimer comprises two thrombin peptide derivatives, each with the amino acid sequence Ala-Gly-Tyr-Lys-Pro-Asp-Glu-Gly-Lys-Arg-Gly-Asp-Ala-Cys-Glu-Gly-Asp-Ser-Gly-Gly-Pro-Phe-Val (SEQ ID NO:6), wherein the thrombin peptide derivatives are covalently linked by a disulfide bond.
11. The method of claim 5 , wherein the peptide dimer is represented by the following structural formula:
12. The method of claim 1 wherein the method further comprises administering to the subject a therapeutically effective amount of an angiogenic growth factor.
13. The method of claim 5 , wherein the method further comprises administering to the subject a therapeutically effective amount of an angiogenic growth factor.
14. The method of claim 11 , wherein the method further comprises administering to the subject a therapeutically effective amount of an angiogenic growth factor.
15. A method of treating radiation damage in a subject comprising administering to the subject a therapeutically effective amount of a 12 to 23 amino acid thrombin peptide derivative comprising a serine esterase conserved sequence and a thrombin binding domain having the sequence Arg-Gly-Asp-Ala (SEQ ID NO: 16).
16. The method of claim 15 , wherein the thrombin peptide derivative comprises an N-terminus which is unsubstituted and a C-terminus which is unsubstituted or a C-terminal amide represented by —C(O)NH 2 and the thrombin peptide derivative comprises a polypeptide having the amino sequence of Arg-Gly-Asp-Ala-Cys-X 1 -Gly-Asp-Ser-Gly-Gly-Pro-X 2 -Val (SEQ ID NO:1), wherein X 1 is Glu or Gln and X 2 is Phe, Met, Leu, His or Val.
17. The method of claim 15 , wherein the thrombin peptide derivative comprises the amino acid sequence of Ala-Gly-Tyr-Lys-Pro-Asp-Glu-Gly-Lys-Arg-Gly-Asp-Ala-Cys-X 1 -Gly-Asp-Ser-Gly-Gly-Pro-X 2 -Val (SEQ ID NO:2), or a fragment thereof, comprising amino acids 10-18 of SEQ ID NO: 2, wherein X 1 is Glu or Gln and X 2 is Phe, Met, Leu, His or Val and the thrombin peptide derivative comprises an N-terminus which is unsubstituted and a C-terminus which is unsubstituted or a C-terminal amide represented by —C(O)NH 2 .
18. A method of treating radiation damage in a subject comprising administering to the subject a therapeutically effective amount of the polypeptide H-Ala-Gly-Tyr-Lys-Pro-Asp-Glu-Gly-Lys-Arg-Gly-Asp-Ala-Cys-Glu-Gly-Asp-Ser-Gly-Gly-Pro-Phe-Val-NH 2 (SEQ ID NO:3).
19. A method of treating radiation damage in a subject comprising administering to the subject a peptide dimer comprising two 12 to 23 amino acid thrombin peptide derivatives which, independently, comprise a serine esterase conserved sequence and a thrombin binding domain having the sequence Arg-Gly-Asp-Ala (SEQ ID NO: 16).
20. The method of claim 19 , wherein the thrombin peptide derivatives each comprise an N-terminus which is unsubstituted; and a C-terminus which is unsubstituted or a C-terminal amide represented by —C(O)NH 2 .
21. The method of claim 19 , wherein the thrombin peptide derivatives each comprise the amino acid sequence Ala-Gly-Tyr-Lys-Pro-Asp-Glu-Gly-Lys-Arg-Gly-Asp-Ala-Cys-X 1 -Gly-Asp-Ser-Gly-Gly-Pro-X 2 -Val (SEQ ID NO:2), wherein X 1 is Glu or Gln and X 2 is Phe, Met, Leu, His or Val, or a fragment thereof, comprising amino acids 10-18 of SEQ ID NO:2, the thrombin peptide derivatives each comprise an N-terminus which is unsubstituted, and a C-terminus which is unsubstituted or a C-terminal amide represented by —C(O)NH 2 , the dimer is essentially free of monomer; the thrombin peptide derivatives are the same, and the thrombin peptide derivatives are covalently linked through a disulfide bond.
22. The method of claim 19 , wherein the thrombin peptide derivatives each comprise the amino acid sequence Ala-Gly-Tyr-Lys-Pro-Asp-Glu-Gly-Lys-Arg-Gly-Asp-Ala-Cys-X 1 -Gly-Asp-Ser-Gly-Gly-Pro-X 2 -Val (SEQ ID NO:2), wherein X 1 is Glu or Gln and X 2 is Phe, Met, Leu, His or Val, the thrombin peptide derivatives each comprise an N-terminus which is unsubstituted; and a C-terminus which is unsubstituted or a C-terminal amide represented by —C(O)NH 2 , the dimer is essentially free of monomer; the thrombin peptide derivatives are the same, and the thrombin peptide derivatives are covalently linked through a disulfide bond.
23. The method of claim 22 , wherein X 1 is Glu and X 2 is Phe.
24. The method of claim 19 , wherein the peptide dimer comprises two thrombin peptide derivatives, each with the amino acid sequence Ala-Gly-Tyr-Lys-Pro-Asp-Glu-Gly-Lys-Arg-Gly-Asp-Ala-Cys-Glu-Gly-Asp-Ser-Gly-Gly-Pro-Phe-Val (SEQ ID NO:6), wherein the thrombin peptide derivatives are covalently linked by a disulfide bond.
25. A method of treating radiation damage in a subject comprising administering to the subject a peptide dimer represented by the following structural formula:
26. The method of claim 15 , wherein the method further comprises administering to the subject a therapeutically effective amount of an angiogenic growth factor.
27. The method of claim 19 , wherein the method further comprises administering to the subject a therapeutically effective amount of an angiogenic growth factor.
28. The method of claim 25 , wherein the method further comprises administering to the subject a therapeutically effective amount of an angiogenic growth factor.