Peptides and methods of use
View Patent ↗The invention provides peptides, including peptides that bind and, optionally, inhibit Protein S, and compositions thereof. The peptides may be used to, e.g., inhibit Protein S activity, enhance thrombin formation in a subject, increase blood clot formation in a subject, treat a blood coagulation disorder in a subject, purify Protein S, and identify a Protein S binding compound.
1. A method for inhibiting Protein S anticoagulatory activity in a subject, the method comprising administering to the subject a peptide in an amount effective to inhibit Protein S anticoagulatory activity, wherein the peptide comprises an amino acid sequence at least 60% identical to the amino acid sequence EYYVSAGWYDYNTDTYYEFE (SEQ ID NO: 2924) and having the structure:
X1001-X1002-X1003-X1004-X1005-X1006-X1007-X1008-X1009-X1010-X1011-X1012-X1013-X1014-X1015-X1016-X1017-X1018-X1019-X1020,
wherein X1001 is A, Bpa, C, D, E, e, F, G, H, I, K, L, M, N, P, p, Q, R, S, T, V, W, or Y;
wherein X1002 is A, C, D, E, F, G, H, I, K, L, M, N, P, p, Q, R, S, T, V, W, Y, or y;
wherein X1003 is A, C, D, E, F, G, H, I, K, L, M, N, P, p, Q, R, S, T, Tle, V, W, Y, or y;
wherein X1004 is F, I, L, Tle, V, or W;
wherein X1005 is A, E, F, G, H, I, K, L, M, R, S, T, V, W, or Y;
wherein X1006 is A, F, G, I, L, Tle, V, W, or Y;
wherein X1007 is G or a;
wherein X1008 is F, 1Ni, 2Ni, Bta, or W;
wherein X1009 is F or Y;
wherein X1010 is D, E, F, H, I, K, L, N, Q, V, W, or Y;
wherein X1011 is F, G, I, K, L, M, R, T, V, W, or Y;
wherein X1012 is A, D, E, F, G, H, I, K, L, N, Q, R, S, T, V, or Y;
wherein X1013 is D, E, F, G, H, I, K, L, Q, R, S, T, V, or W;
wherein X1014 is D, E, or H;
wherein X1015 is D, E, H, I, K, M, Q, R, S, T, V, or W;
wherein X1016 is F, H, W, or Y;
wherein X1017 is D, E, G, H, I, T, W, or Y;
wherein X1018 is A, D, E, G, H, I, K, L, M, P, Q, R, S, T, V, or W;
wherein X1019 is F or W; and
wherein X1020 is A, C, D, E, e, F, G, H, I, K, L, M, N, P, p, Q, R, S, T, V, W, or Y.
2. A method of treating a subject suffering from a blood coagulation disorder associated with hypocoagualtion or being at risk of suffering from a blood coagulation disorder associated with hypocoagualtion, the method comprising administering to the subject a peptide comprising an amino acid sequence at least 60% identical to the amino acid sequence EYYVSAGWYDYNTDTYYEFE (SEQ ID NO: 2924) and having the structure:
X1001-X1002-X1003-X1004-X1005-X1006-X1007-X1008-X1009-X1010-X1011-X1012-X1013-X1014-X1015-X1016-X1017-X1018-X1019-X1020,
wherein X1001 is A, Bpa, C, D, E, e, F, G, H, I, K, L, M, N, P, p, Q, R, S, T, V, W, or Y;
wherein X1002 is A, C, D, E, F, G, H, I, K, L, M, N, P, p, Q, R, S, T, V, W, Y, or y;
wherein X1003 is A, C, D, E, F, G, H, I, K, L, M, N, P, p, Q, R, S, T, Tle, V, W, Y, or y;
wherein X1004 is F, I, L, Tle, V, or W;
wherein X1005 is A, E, F, G, H, I, K, L, M, R, S, T, V, W, or Y;
wherein X1006 is A, F, G, I, L, Tle, V, W, or Y;
wherein X1007 is G or a;
wherein X1008 is F, 1Ni, 2Ni, Bta, or W;
wherein X1009 is F or Y;
wherein X1010 is D, E, F, H, I, K, L, N, Q, V, W, or Y;
wherein X1011 is F, G, I, K, L, M, R, T, V, W, or Y;
wherein X1012 is A, D, E, F, G, H, I, K, L, N, Q, R, S, T, V, or Y;
wherein X1013 is D, E, F, G, H, I, K, L, Q, R, S, T, V, or W;
wherein X1014 is D, E, or H;
wherein X1015 is D, E, H, I, K, M, Q, R, S, T, V, or W;
wherein X1016 is F, H, W, or Y;
wherein X1017 is D, E, G, H, I, T, W, or Y;
wherein X1018 is A, D, E, G, H, I, K, L, M, P, Q, R, S, T, V, or W;
wherein X1019 is F or W; and
wherein X1020 is A, C, D, E, e, F, G, H, I, K, L, M, N, P, p, Q, R, S, T, V, W, or Y.
3. The method of claim 1 , wherein X1004 is V, X1005 is S, X1006 is A, X1007 is G, X1008 is W, and X1009 is Y.
4. The method of claim 2 , wherein X1004 is V, X1005 is S, X1006 is A, X1007 is G, X1008 is W, and X1009 is Y.
5. The method of claim 1 ,
wherein X1003 is A, E, F, G, H, I, K, L, N, P, R, T, V, W, y, or Y; and
wherein X1002 is A, D, E, F, G, H, I, K, L, N, P, R, T, V, W, y, or Y.
6. The method of claim 2 ,
wherein X1003 is A, E, F, G, H, I, K, L, N, P, R, T, V, W, y, or Y; and
wherein X1002 is A, D, E, F, G, H, I, K, L, N, P, R, T, V, W, y, or Y.
7. The method of claim 1 , wherein the peptide comprises an amino acid sequence at least about 80% identical to the amino acid sequence EYYVSAGWYDYNTDTYYEFE (SEQ ID NO: 2924).
8. The method of claim 2 , wherein the peptide comprises an amino acid sequence at least about 80% identical to the amino acid sequence EYYVSAGWYDYNTDTYYEFE (SEQ ID NO: 2924).
9. The method of claim 1 , wherein the peptide comprises an amino acid sequence at least about 90% identical to the amino acid sequence EYYVSAGWYDYNTDTYYEFE (SEQ ID NO: 2924).
10. The method of claim 2 , wherein the peptide comprises an amino acid sequence at least about 90% identical to the amino acid sequence EYYVSAGWYDYNTDTYYEFE (SEQ ID NO: 2924).
11. The method of claim 9 , wherein the amino acid sequence comprises the amino acid sequence EYYVSAGWYDYNTDTYYEFE (SEQ ID NO: 2924).
12. The method of claim 10 , wherein the amino acid sequence comprises the amino acid sequence EYYVSAGWYDYNTDTYYEFE (SEQ ID NO: 2924).
13. The method of claim 1 , wherein the peptide consists of an amino acid sequence at least about 80% identical to the amino acid sequence EYYVSAGWYDYNTDTYYEFE (SEQ ID NO: 2924).
14. The method of claim 2 , wherein the peptide consists of an amino acid sequence at least about 80% identical to the amino acid sequence EYYVSAGWYDYNTDTYYEFE (SEQ ID NO: 2924).
15. The method of claim 1 , wherein the peptide is conjugated to a polyethylene glycol (PEG) moiety, albumin, an antibody or fragment thereof, hydroxyethyl starch, a multimer comprising proline, alanine, serine, or a combination thereof, a C12-C18 fatty acid, or polysialic acid.
16. The method of claim 2 , wherein the peptide is conjugated to a polyethylene glycol (PEG) moiety, albumin, an antibody or fragment thereof, hydroxyethyl starch, a multimer comprising proline, alanine, serine, or a combination thereof, a C12-C18 fatty acid, or polysialic acid.
17. The method of claim 1 , wherein the peptide is conjugated or attached to a moiety selected from the group consisting of Bpa, Bpa-K(Bio)-C, C(Atf-Bio), C(Atf-LC-Bio), C(FeBABE), C(MalCy5), C(NEM), C(PEG), K, K(Ac), K(Ttds), K(Ttds-γGlu), K(Glutaric Acid), K(Ttds-Maleimide), T, Ttds, or Ttds-K(Bio).
18. The method of claim 2 , wherein the peptide is conjugated or attached to a moiety selected from the group consisting of Bpa, Bpa-K(Bio)-C, C(Atf-Bio), C(Atf-LC-Bio), C(FeBABE), C(MalCy5), C(NEM), C(PEG), K, K(Ac), K(Ttds), K(Ttds-γGlu), K(Glutaric Acid), K(Ttds-Maleimide), T, Ttds, or Ttds-K(Bio).
19. A method for binding a peptide to Protein S in a subject, the method comprising administering to the subject a peptide in an amount effective to bind Protein S, wherein the peptide comprises an amino acid sequence at least 60% identical to the amino acid sequence EYYVSAGWYDYNTDTYYEFE (SEQ ID NO: 2924) and having the structure:
X1001-X1002-X1003-X1004-X1005-X1006-X1007-X1008-X1009-X1010-X1011-X1012-X1013-X1014-X1015-X1016-X1017-X1018-X1019-X1020,
wherein X1001 is A, Bpa, C, D, E, e, F, G, H, I, K, L, M, N, P, p, Q, R, S, T, V, W, or Y;
wherein X1002 is A, C, D, E, F, G, H, I, K, L, M, N, P, p, Q, R, S, T, V, W, Y, or y;
wherein X1003 is A, C, D, E, F, G, H, I, K, L, M, N, P, p, Q, R, S, T, Tle, V, W, Y, or y;
wherein X1004 is F, I, L, Tle, V, or W;
wherein X1005 is A, E, F, G, H, I, K, L, M, R, S, T, V, W, or Y;
wherein X1006 is A, F, G, I, L, Tle, V, W, or Y;
wherein X1007 is G or a;
wherein X1008 is F, 1Ni, 2Ni, Bta, or W;
wherein X1009 is F or Y;
wherein X1010 is D, E, F, H, I, K, L, N, Q, V, W, or Y;
wherein X1011 is F, G, I, K, L, M, R, T, V, W, or Y;
wherein X1012 is A, D, E, F, G, H, I, K, L, N, Q, R, S, T, V, or Y;
wherein X1013 is D, E, F, G, H, I, K, L, Q, R, S, T, V, or W;
wherein X1014 is D, E, or H;
wherein X1015 is D, E, H, I, K, M, Q, R, S, T, V, or W;
wherein X1016 is F, H, W, or Y;
wherein X1017 is D, E, G, H, I, T, W, or Y;
wherein X1018 is A, D, E, G, H, I, K, L, M, P, Q, R, S, T, V, or W;
wherein X1019 is F or W; and
wherein X1020 is A, C, D, E, e, F, G, H, I, K, L, M, N, P, p, Q, R, S, T, V, W, or Y.