CHOLESTEROL DERIVATIVES OF INHIBITORS OF VIRAL FUSION
The present invention relates to compounds comprising at least ten contiguous amino acids of the HR2 domain of a Type 1 viral fusogenic protein of an enveloped virus, or a derivative thereof, attached at the C-terminal to cholesterol or a derivative thereof; or a pharmaceutically acceptable salt thereof which inhibit viral fusion. Thus compounds of the invention are useful to prevent or treat diseases caused by an enveloped virus.
1 . An inhibitor of viral fusion comprising at least ten contiguous amino acids of the HR2 domain of a Type 1 viral fusogenic protein of an enveloped virus, or a derivative thereof, attached at the C-terminal to cholesterol or a derivative thereof; or a pharmaceutically acceptable salt thereof; wherein the contiguous amino acids do not extend beyond the HR2 domain.
2 . (canceled)
3 . An inhibitor according to claim 1 wherein the virus is human immunodeficiency virus 1 (HIV-1).
4 . An inhibitor according to claim 1 which comprises at least 15 contiguous amino acids of the HR2 domain.
5 . An inhibitor according to claim 1 which comprises at least 25 contiguous amino acids of the HR2 domain.
6 . An inhibitor according to claim 1 which comprises at least 30 contiguous amino acids of the HR2 domain.
7 . An inhibitor according to claim 6 which comprises amino acids 628-661 of gp41 of HIV-1.
8 . (canceled)
9 . An inhibitor according to claim 1 wherein the C-terminus of the viral protein is amidated.
10 . An inhibitor according to claim 1 having a linker between the fusogenic protein and the cholesterol or a derivative thereof, the linker comprising two or more amino acids.
11 . An inhibitor according to claim 10 wherein the linker is (Gly) n+1 , (GlySerGly) n or (Gly-Pro) n wherein n is 1 or greater.
12 . An inhibitor according to claim 11 wherein the linker comprises GlySerGly.
13 . An inhibitor according to claim 10 wherein the linker comprises a moiety —(OCH 2 CH 2 ) m — wherein m is an integer from 1 to 15.
14 . An inhibitor according to claim 10 wherein cysteine is added to the C-terminal of the amino acids of the linker.
15 . An inhibitor according to claim 14 wherein the linker is attached to the oxygen of the cholesterol or derivative thereof via the sulphur atom of the cysteine residue by the moiety —CH 2 C(O)— or —CH 2 C(O)NHCH 2 CH 2 (OCH 2 CH 2 ) 4 C(O)—.
16 . An inhibitor according to claim 1 which comprises cholesterol.
17 . (canceled)
18 . A pharmaceutical composition comprising an inhibitor of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
19 . A pharmaceutical composition according to claim 18 which is a pessary, vaginal ring, cream or gel.
20 - 24 . (canceled)
25 . A method of treating a subject suffering from infection by an enveloped virus which comprises administering to that subject a therapeutically effective amount of an inhibitor of claim 1 , or a pharmaceutically acceptable salt thereof.
26 . A method of preventing a subject prone to infection by an enveloped virus from infection by that virus which comprises administering to that subject a prophylactically effective amount of an inhibitor of claim 1 , or a pharmaceutically acceptable salt thereof.
27 . A combination of an inhibitor of claim 1 , or a pharmaceutically acceptable salt thereof, and another compound which treats or inhibits infection by an enveloped virus.
28 . The method of claim 25 wherein the virus is HIV-1.
29 . The method of claim 26 wherein the virus is HIV-1.