Procoagulant peptides

1. A peptide or peptide derivative comprising:

(i) an amino acid sequence comprising imfwydcye (SEQ ID NO: 431); or

(ii) a variant amino acid sequence comprising one, two, three, four, five or six amino acid substitutions in imfwydcye (SEQ ID NO: 431), said variant amino acid sequence comprising X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 , wherein X 1 , when present, is c, s, y, i, D-Pen, C, t, D-Nva, D-Nle or k; X 2 is i, y, w or d; X 3 is c or m; X 4 is f, t, v or c; X 5 is w or c; X 6 is y or c; X 7 is d, e or f; X 8 is c, e, f, y or d; X 9 is y or w; and X 10 is e or i (SEQ ID NO: 433);

wherein said peptide or peptide derivative has procoagulant activity.

2. The peptide or peptide derivative of claim 1 comprising an amino acid sequence comprising cimfwydcye (SEQ ID NO: 432).

3. The peptide or peptide derivative of claim 1 , 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 (SEQ ID NO: 434).

4. The peptide or peptide derivative of claim 3 , 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 (SEQ ID NO: 435).

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

6. The peptide derivative of claim 2 which is acetylated at the N-terminus, amidated at the C-terminus and/or PEGylated at either terminus.

7. The peptide or peptide derivative of claim 1 which is cyclic.

8. The peptide or peptide derivative of claim 1 comprising or consisting of:

Ac-cimfwydeye-NH 2 (SEQ ID NO: 436), Disulphide-Dimer(Ac-cimfwydeye-NH 2 ) 2 (SEQ ID NO: 437), Ac-TTDS-(cymfwydc)-ye-NH 2 (SEQ ID NO: 438), K-TTDS-(cymfwydc)-ye-NH 2 (SEQ ID NO: 439), Ac-cimtwydcye-NH 2 (SEQ ID NO: 440), Ac-cimvwydcye-NH 2 (SEQ ID NO: 441), cymfwydcye (SEQ ID NO: 442), Ac-(cymfwydc)-yeG-NH 2 (SEQ ID NO: 443), Ac-(D-Pen)imfwydeye-NH 2 (SEQ ID NO: 444), O(CH 2 —CH 2 —O—CH 2 —CO-imfwydeye-NH 2 ) 2 (SEQ ID NO: 445), Pyridine-3,5-(CO-imfwydeye-NH 2 ) 2 (SEQ ID NO: 446), H 2 N-E-TTDS-(cymfwydc)-ye-NH 2 (SEQ ID NO: 447), Ac-(cymfwydc)-yeK (SEQ ID NO: 448), Ac-(cymfwydc)-ye-TTDS-K (SEQ ID NO: 449), Ac-simfwydeye-NH 2 (SEQ ID NO: 450), Ac-simfwydeye-NH 2 (SEQ ID NO: 451), Ac-ydmcwcefyi-NH 2 (SEQ ID NO: 452), Ac-idmccyfywe-NH 2 (SEQ ID NO: 453), Ac-cimfwyddye-NH 2 (SEQ ID NO: 454), Ac-(cymfwydc)-ye (SEQ ID NO: 455), Ac-(cymfwydc)-ye-TTDS-NH 2 (SEQ ID NO: 456), Ac-TTDS-(cymfwydc)-ye-TTDS-NH 2 (SEQ ID NO: 457), K-(cymfwydc)-ye-NH 2 (SEQ ID NO: 458), Ac-K-(cymfwydc)-ye-NH 2 (SEQ ID NO: 459), E-(cymfwydc)-ye-NH 2 (SEQ ID NO: 460), Ac-K-TTDS-(cymfwydc)-ye-NH 2 (SEQ ID NO: 461), Ac-(cymfwydc)-yeK-NH 2 (SEQ ID NO: 462), Ac-(cymfwydc)-ye-TTDS-K-NH 2 (SEQ ID NO: 463), Ac-(cymfwydc)-ye-TTDS-E-NH 2 (SEQ ID NO: 464), Ac-timfwydeye-NH 2 (SEQ ID NO: 465), Ac-(cimfwydc)-ye-NH 2 (SEQ ID NO: 466), Ac-(cymfwydc)-ye-NH 2 (SEQ ID NO: 467), Ac-(cwmfwydc)-ye-NH 2 (SEQ ID NO: 468), Ac-cicfwydcye-NH 2 (SEQ ID NO: 469), Ac-(D-Nva)imfwydeye-NH 2 (SEQ ID NO: 470), Ac-(D-Nle)imfwydeye-NH 2 (SEQ ID NO: 471), Ac-(Cys)imfwydeye-NH 2 (SEQ ID NO: 472), (cymfwydc)-ye-NH 2 (SEQ ID NO: 473), TTDS-(cymfwydc)-ye-TTDS-NH 2 (SEQ ID NO: 474), Ac-kimfwydeye-NH 2 (SEQ ID NO: 475), 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 peptide or peptide derivative as defined in claim 1 conjugated to a further peptide or 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 further peptide or peptide derivative, and wherein the dual peptide has procoagulant activity.

10. A pharmaceutical composition comprising the peptide or peptide derivative of claim 1 and one or more pharmaceutically acceptable excipients, carriers and/or diluents.

11. The pharmaceutical composition of claim 10 suitable for subcutaneous, nasal, buccal, oral, pulmonary, or intravenous administration.

12. A method of treating a patient having a deficiency in FV, FVII, FVIII, FX and/or FXI comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of claim 10 .

13. A method of treating a patient having a deficiency in FV, FVII, FVIII, FX and/or FXI comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of claim 11 .

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

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

16. The peptide or peptide derivative of 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.