Claims
- 1. A method for treating a patient having a condition mediated by neurotoxicity, neurodegeneration or neurological damage, comprising administering to said patient a therapeutically effective amount of a peptide comprising one or more monomeric peptides of 8 to about 40 amino acids in length that bind to EPO receptor, each monomeric peptide comprising a sequence of amino acids X4X5XaXbX6XcXdX7 (SEQ ID NO: 47), wherein
Xa is G or A; Xb is P or A; Xc is T or A; Xd is selected from W, A, and F; X4 is selected from R, H, Y, L, and W, or X4 is nonexistent; X5 is selected from F, M, and I; X6 is independently selected from the 20 genetically coded L-amino acids or the stereoisomeric D-amino acids; and X7 is selected from D, V, E, I, and L.
- 2. The method of claim 1, wherein said sequence is X4X5GPX6TWX7 (SEQ ID NO: 48.
- 3. The method of claim 2, wherein said sequence is X3X4X5GPX6TWX7X8 (SEQ ID NO: 1), wherein
X3 is selected from C, E, A, α-amino-γ-bromobutyric acid, and homocysteine (Hoc); and, X8 is selected from C, K, A, α-amino-γ-bromobutyric acid, and homocysteine (Hoc).
- 4. The method of claim 3 with the proviso that either X3 or X8 is C or homocysteine (Hoc).
- 5. The method of claim 4 wherein X3 or X8 is C.
- 6. The method of claim 3 wherein
X3 is selected from C, E, and A; X4 is selected from R, H, and Y, or X4 is nonexistent; X6 is selected from V, L, I, M, E, and A; and X7 is D or V; and X8 is selected from C, K and A.
- 7. The method of claim 3 wherein said peptide is a dimer of each of said monomeric peptides comprising a sequence of amino acids YX2X3X4X5GPX6TWX7X8 (SEQ ID NO: 2), wherein
X2 and X6 are each independently selected from the 20 genetically coded L-amino acids; X3 is C; and X8 is C.
- 8. The method of claim 7 wherein
X2 is selected from L S H M A and I, or X2 is nonexistent; and X6 is selected from V, L, I, M, E, and A.
- 9. The method of claim 7 wherein each of said monomeric peptides comprises a sequence of amino acids X1YX2X3X4X5GPX6TWX7X8X9X10X11 (SEQ ID NO: 3), wherein each of X1, X2, X6, X9, X10, and X11, is independently selected from the 20 genetically coded L-amino acids.
- 10. The peptide dimer of claim 9 wherein
X3 is selected from C, E, and A; X4 is selected from R, H, and Y, or X4 is nonexistent; X7 is D or V; X8 is C or K. X9 is K, G, L, Q, R, S, or T; and X10 is A, G, P, R, or Y.
- 11. The method of claim 10 wherein
X1 is D, E, L, N, S, T or V; X2 is selected from L, S, H, M, A, and I, or X2 is nonexistent; X9 is selected from K, Q, R, S, and G; and X10 is selected from P, Y, and A.
- 12. The method of claim 3 wherein said peptide is a dimer of each of said monomenc peptides comprising a sequence of amino acids X′X2X3X4X5GPX6TWX7X8 (SEQ ID NO: 49), wherein X′ is selected from D-Tyr, p-NO2-Phe, p-NH2-Phe, p-F-Phe, p-I-Phe, and 3,5-dibromo-Tyr.
- 13. The method of claim 12 wherein said sequence is X′CHFGPLTWVC.
- 14. The method of claim 1 wherein each of said monomeric peptides comprise a sequence independently selected from
- 15. The method of claim 14 wherein each of said monomeric peptides is independently selected from:
- 16. The method of claim 1 wherein said peptide is a dimer formed by a polyethylene glycol linker through a covalent bond.
- 17. The method of claim 16 wherein each monomeric peptides of said dimer are covalently bound N-terminus to N-terminus.
- 18. The method of claim 16 wherein each monomeric peptides of said dimer are covalently bound N-terminus to C-terminus.
- 19. The method of claim 1 wherein said monomeric peptides are dimerized on activated benodiazepins, oxazalones, azalactones, aminimides or diketopiperazine.
- 20. The method of claim 19 wherein said monomeric peptides are covalently bound N-terminus to N-terminus.
- 21. The method of claim 19 wherein said monomeric peptides are covalently bound N-terminus to C-terminus.
- 22. The peptide of claim 2, which comprises least one peptide dimer.
- 23. A method of activating a cell surface receptor to induce neuroprotective biological activity comprising contacting a dimer of peptides of claim 2 with said receptor thereby inducing said neuroprotective biological activity.
- 24. The method of claim 23 wherein said cell surface receptor is contacted with said dimer in vitro or in vivo.
- 25. The method of claim 23 wherein said cell surface receptor is EPO receptor.
- 26. The method of claim 23 wherein said peptide dimer is a cell surface receptor agonist selected form a group consisting of a GH agonist, PDGF agonist, EGF agonist, G-CSF agonist, TPO (thrombopoietin) agonist, VEGF agonist, FGF agonist, insulin agonist, IL-3 agonist, IL-5 agonist, IL-6 agonist and IL-2 agonist.
- 27. The method of claim 23 wherein said agonist comprises a sequence of amino acids YX2X3X4X5GPX6TWX7X8 (SEQ ID NO: 2) wherein each of X2 and X6 is independently selected from the 20 genetically coded L-amino acids; X3 is C; X4 is R, H, L or W; X5 is M, F or I; X7 is D, E, I, L or V; and X8 is C.
- 28. The method of claim 23 wherein said agonist comprises a sequence of amino acids X1YX2X3X4X5GPX6TWX7X8X9X10X11 (SEQ ID NO: 3) wherein each of X1, X2, X6, X9, X10, and X11 is independently selected from any one of the 20 genetically coded Lamino acids; X3is C; X4 is R, H, L or W; X5 is M, F or I; X7 is D, E, I, L or V; and X8is C.
- 29. The method of claim 23 wherein said agonist comprises a sequence of amino acids X1YX2X3X4X5GPX6TWX7X8X9X10X11 (SEQ ID NO: 3) wherein each of X1, X2, and X11, is independently selected from any one of the 20 genetically coded L-amino acids; X3 is C; X4 is R or H; X5 is F or M; X6 is I, L, T, M or V; X7 is D or V; X9 is G, K, L, Q, R, S, or T; and X10 is A, G, P, R, or Y.
- 30. The method of claim 23 wherein said agonist comprises a sequence of amino acids X1YX2X3X4X5GPX6TWX7X8X9X10X11 (SEQ ID NO: 3) wherein X1 is D, E, L, N, S, T or V; X2 is A, H, K, L, M, S, or T; X3 is C; X4 is R or H; X5 is M, F or I; X6 and X11 are independently any one of the 20 genetically coded L-amino acids; X7 is D, E, I, L or V; X8 is C; X9 is K, R, S, or T; and X10 is P.
- 31. The method of claim 23 wherein said agonist is selected from a group consisting of:
- 32. The method of claim 23 wherein said peptide dimers are formed with a polyethylene glycol linker through a covalent bond.
- 33. A method of preparing a cell surface receptor agonist comprising dimerizing a cell surface antagonist.
- 34. The method of claim 33 wherein said cell surface antagonist receptor is a GH antagonist, PDGF antagonist, EGF antagonist, G-CSF antagonist, EGF antagonist, GM-CSF antagonist, TPO antagonist, VEGF antagonist, FGF antagonist, insulin antagonist, IL-3 antagonist, IL-5 antagonist, IL-6 antagonist, or an IL-2 antagonist.
- 35. The method of claim 33 wherein said cell surface receptor antagonist is an EPO-R antagonist.
- 36. The method of claim 35 wherein said antagonist comprises a sequence of amino acids (X?X2)nX3X4X5GPX6TWX7X8 (SEQ ID NO: 19) wherein X6 is selected from the 20 genetically coded L-amino acids; X3 is C; X4 is R, H, L or W; X5, is M, F or I; X7, is D, E, I, L or V; X8 is C; X2 is selected from the 20 genetically coded L-amino acids, n is 0 or 1 and X? is any of the 20 genetically coded L-amino acids except Y (tyrosine).
- 37. The method of claim 33 where said antagonist is SCHFGPLTWVCK (SEQ ID NO: 18).
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional Application Ser. No. 60/207654, filed May 26, 2000.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60207654 |
May 2000 |
US |