Biologically active peptides

1. A method of treating a patient having a deficiency in FV, FVII, FVIII, FX and/or FXI, said method comprising administering to the patient a therapeutically effective amount of a peptide or peptide derivative comprising:

(i) an amino acid sequence comprising imfwydcye; or

(ii) a variant amino acid sequence comprising one, two, three, or four amino acid substitutions in imfwydcye; wherein the variant amino acid sequence comprises an amino acid sequence comprising X 1 X 2 X 3 X 4 wydX 8 ye, wherein X 1 , when present, is c, C, D-Pen or s; X 2 is i, y or w; X 3 is c or m; X 4 is f, t, or v; and X 8 is c or e;

wherein said peptide or peptide derivative has procoagulant activity; and

wherein said patient has inhibitor antibodies against FV, FVII, FVIII, FX and/or FXI.

2. The method of treating a patient having a deficiency in FV, FVII, FVIII, FX and/or FXI according to claim 1 , wherein said administering is selected from the group consisting of intravenous, intraperitoneal, subcutaneous, nasal, buccal, oral and pulmonary delivery.

3. The method according to claim 1 , wherein the peptide or peptide derivative comprises an amino acid sequence comprising cimfwydcye.

4. The method according to claim 1 , wherein the variant amino acid sequence comprises an amino acid sequence comprising X 1 X 2 mX 4 wydX 8 ye, wherein X 1 , when present, is c, C, or D-Pen; X 2 is i or y; X 4 is f, t, or v; and X 8 is c or e.

5. The method of according to claim 1 , wherein the peptide or peptide derivative is acetylated at the N-terminus, amidated at the C-terminus and/or PEGylated at either terminus.

6. The method of according to claim 3 , wherein the peptide or peptide derivative is acetylated at the N-terminus, amidated at the C-terminus and/or PEGylated at either terminus.

7. The method of according to claim 1 , wherein the peptide or peptide derivative is cyclic.

8. The method of according to claim 1 , wherein the peptide or peptide derivative comprises or consists of: Ac-cimfwydeye-NH 2 , Disulphide-Dimer(Ac -cimfwydeye-NH 2 ) 2 , Ac-TTDS-(cymfwydc)-ye-NH 2 , K-TTDS-(cymfwydc)-ye-NH 2 , Ac -cimtwydcye-NH 2 , Ac-cimvwydcye-NH 2 , cymfwydcye, Ac-(cymfwydc)-yeG-NH 2 , Ac-(D -Pen)imfwydeye-NH 2 , O(CH 2 -CH 2 -O-CH 2 -CO-imfwydeye-NH 2 ) 2 , Pyridine-3,5-(CO-imfwydeye-NH 2 ) 2 , H 2 N-E-TTDS-(cymfwydc)-ye-NH 2 , Ac-(cymfwydc)-yeK, Ac-(cymfwydc)-ye-TTDS-K, Ac-simfwydeye-NH 2 , Ac-simfwydeye-NH 2 , Ac-(cymfwydc)-ye, Ac-(cymfwydc)-ye-TTDS-NH 2 , Ac-TTDS-(cymfwydc)-ye-TTDS-NH 2 , K-(cymfwydc)-ye-NH 2 , Ac-K-(cymfwydc)-ye-NH 2 , E-(cymfwydc)-ye-NH 2 , Ac-K-TTDS-(cymfwydc)-ye-NH 2 , Ac-(cymfwydc)-yeK-NH 2 , AC-(cymfwydc)-ye-TTDS-K-NH 2 , Ac-(cymfwydc)-ye-TTDS-E-NH 2 , AC-(cimfwydc)-ye-NH 2 , Ac-(cymfwydc)-ye-NH 2 , Ac-(cwmfwydc)-ye-NH 2 , Ac-cicfwydcye-NH 2 , Ac-(D-Nva)imfwydeye-NH 2 , Ac-(D-Nle)imfwydeye-NH 2 , Ac-(Cys)imfwydeye-NH 2 , (cymfwydc)-ye-NH 2 , TTDS-(cymfwydc)-ye-TTDS-NH 2 ,

wherein -TTDS- is 4,7,10-trioxa-1,13-tridecanediamine, (D-Pen) is D-penicillamine, (D-Nva) is D-norvaline, (D-Nle) is D-norleucine.

9. The method of according to claim 1 , wherein the peptide or peptide derivative has a molecular weight of between 0.5 and 3.5 kD.

10. The method of according to claim 1 , wherein the peptide or peptide derivative has a procoagulant activity, and the procoagulant activity is a thrombin generation time of 25, 50 or 100 μM of the peptide or peptide derivative equivalent to that of at least 100 mU/mL Factor Eight Inhibitor Bypassing Activity (FEIBA).

11. The method of according to claim 10 , wherein the peptide or peptide derivative has a procoagulant activity, and the procoagulant activity is a thrombin generation time of 25, 50 or 100 μM of the peptide or peptide derivative equivalent to that of at least 300 mU/mL Factor Eight Inhibitor Bypassing Activity (FEIBA).

12. The method of according to claim 10 , wherein the peptide or peptide derivative has a procoagulant activity, and the procoagulant activity is a thrombin generation time of 25, 50 or 100 μM of the peptide or peptide derivative equivalent to that of at least 900 mU/mL Factor Eight Inhibitor Bypassing Activity (FEIBA).

13. The method of according to claim 10 , wherein the peptide or peptide derivative has a procoagulant activity, and the procoagulant activity is a thrombin generation time of 25, 50 or 100 μM of the peptide or peptide derivative equivalent to that of at least 1200 mU/mL Factor Eight Inhibitor Bypassing Activity (FEIBA).

14. The method of according to claim 1 , wherein the peptide or peptide derivative has a procoagulant activity, and the procoagulant activity is a thrombin generation time of 25, 50 or 100 μM of the peptide or peptide derivative in a Defined Intrinsic Thrombin Generation Assay peaking within 30 minutes.

15. The method of according to claim 1 , wherein the peptide or peptide derivative has a procoagulant activity, and the procoagulant activity is a thrombin generation time of 25, 50 or 100 μM of the peptide or peptide derivative in a Defined Intrinsic Thrombin Generation Assay peaking within 15 minutes.

16. The method of according to claim 1 , wherein the peptide or peptide derivative has a procoagulant activity, and the procoagulant activity is a thrombin generation time of 25, 50 or 100 μM of the peptide or peptide derivative in a Defined Intrinsic Thrombin Generation Assay peaking within 10 minutes.

17. The method of according to claim 1 , wherein the peptide or peptide derivative can at least partially compensate for the absence of biologically active FVIII when administered in an animal model of severe human hemophilia A.

18. The method of according to claim 1 , wherein the peptide or peptide derivative has a stability in human plasma at 30 minutes of at least 50%.

19. The method of according to claim 1 , wherein the peptide or peptide derivative has a stability in human plasma at 30 minutes of at least 70%.

20. The method of according to claim 1 , wherein the peptide or peptide derivative has a stability in human plasma at 30 minutes of at least 80%.

21. The method of according to claim 1 , wherein the peptide or peptide derivative has a stability in human plasma at 30 minutes of at least 90%.

22. The method of according to claim 1 , wherein the peptide or peptide derivative has an aqueous solubility in phosphate buffered saline pH 7.4 of at least 25 μM.

23. The method of according to claim 1 , wherein the peptide or peptide derivative has an aqueous solubility in phosphate buffered saline pH 7.4 of at least 60 μM.

24. The method of according to claim 1 , wherein the peptide or peptide derivative has an aqueous solubility in phosphate buffered saline pH 7.4 of at least 100 μM.

25. The method of according to claim 1 , wherein the peptide or peptide derivative is conjugated to a second peptide or second peptide derivative as defined in claim 1 to form a dual peptide, wherein the peptide or peptide derivative may be the same as or different from the second peptide or second peptide derivative, and wherein the dual peptide has procoagulant activity.