Inhibitors of hepatitis C virus

Abstract

The present invention relates to methods that employ peptides or peptide derivatives to inhibit hepatitis C virus infection. The present invention is based in part on the discovery that E2 envelope glycoprotein of hepatitis C virus has previously undescribed domains that are important for interactions with cellular or viral proteins that are necessary for early steps in HCV infection. The present invention provides peptides and methods of treatment and prophylaxis of diseases induced by hepatitis C virus and related viruses.

1 . A pharmaceutical composition comprising one or more peptides selected from the group consisting of:
 a) a peptide having the sequence of any of SEQ ID NO:1 to SEQ ID NO:6;   b) a peptide homologous to any one of SEQ ID NO:1 to SEQ ID NO:6 from another hepatitis C virus strain or from hepatitis GB virus; and   c) a peptide functionally equivalent to any one of SEQ ID NO:1 to SEQ ID NO:6,   wherein the functionally equivalent peptide is identical to at least one of SEQ ID NO:1 to SEQ ID NO:6 except that one or more amino acid residues has been substituted with a homologous amino acid, resulting in a functionally silent change, or one or more amino acids has been deleted.   
     
     
         2 . A pharmaceutical composition comprising at least one peptide selected from one or more of the following:
 a) a peptide having the amino acid sequence one or more of SEQ ID NO:1 to SEQ ID NO:6, wherein the N-terminal moiety is an amino group and the C-terminal moiety is a carboxyl group;   b) a peptide having the sequence of any of SEQ ID NO:1 to SEQ ID NO:6, wherein the N-terminal moiety is not an amino group and/or the C-terminal moiety is not a carboxyl group, wherein in place of an amino moiety the N-terminal moiety is selected from the group consisting of: an acetyl group, a hydrophobic group, carbobenzoxyl group, dansyl group, a t-butyloxycarbonyl group, or a macromolecular carrier group, and/or wherein in place of a carboxyl moiety the C-terminal moiety is selected from the group consisting of an amido group, a hydrophobic group, t-butyloxycarbonyl group or a macromolecular group;   c) a peptide having the sequence of any of SEQ ID NO:1 to SEQ ID NO:6, wherein at least one bond linking adjacent amino acid residues is a non-peptide bond;   d) a peptide having the sequence of any of SEQ ID NO:1 to SEQ ID NO:6, wherein at least one amino acid residue is in the D-isomer configuration;   e) a peptide as in part “a)” or “b)” except that at least one amino acid has been substituted for by a different amino acid; or   f) a functional fragment of a peptide as set out in any of parts “a)” to “e)”, having at least 3 contiguous nucleotides of any one of SEQ ID NO:1 to SEQ ID NO:42.   
     
     
         3 . The composition of  claim 2  wherein at least one peptide has an amino acid sequence is selected from one or more of the group consisting of SEQ ID NO: 1, 2, 3, 4, 5 and 6. 
     
     
         4 . The composition of  claim 3  wherein the terminal moiety on the N-terminal amino acid is an acetyl group, a hydrophobic group a carbobenzoxyl group, a dansyl group, a t-butyloxycarbonyl group, or a macromolecular carrier group; and/or the terminal moiety on C-terminal amino acid is a hydrophobic group, a t-butyloxycarbonyl group or a macromolecular group. 
     
     
         5 . The composition of  claim 3  wherein the terminal moiety on the N-terminal amino acid is a macromolecular carrier group selected from a lipid conjugate, polyethylene glycol, or a carbohydrate; and/or the terminal moiety on the C-terminal amino acid is a macromolecular carrier group selected from a lipid conjugate, polyethylene glycol, or a carbohydrate. 
     
     
         6 . The composition of  claim 3  wherein at least one bond is a non-peptide bond selected from the group consisting of an imido bond, an ester bond, a hydrazine bond, a semicarbazoide bond and an azo bond. 
     
     
         7 . The composition of 3 wherein at least one amino acid is a D-isomer amino acid. 
     
     
         8 . The composition of  claim 3  wherein terminal moiety on the N-terminal amino acid group is an amino group and the terminal moiety on the C-terminal amino acid is a carboxyl group. 
     
     
         9 . The composition of  claim 8  wherein the peptide is selected from one or more of the group consisting of SEQ ID NO: 1, 2, 3, 4, 5, and 6. 
     
     
         10 . The composition of  claim 1  wherein at least one peptide is selected from the group of peptides having a sequence selected from the sequences of SEQ ID NO:7-42. 
     
     
         11 . A method of treating or preventing hepatitis C virus infection comprising administering to the patient an effective amount of a pharmaceutical composition according to any of  claims 1 - 10 . 
     
     
         12 . A substantially purified antibody specific for a peptide as described in any of  claims 1 - 10 . 
     
     
         13 . A method of treating or preventing hepatitis C virus infection comprising administering to a patient one or more peptides according to any of  claims 1 - 9  and/or an antibody according to  claim 11  and/or one or more peptides and/or one or more antibodies targeted to inhibiting the membrane fusion step mediated by hepatitis C virus envelope protein 1. 
     
     
         14 . The method of  claim 13 , wherein the combination of the compounds from  claims 1 - 9  and/or 11 with the peptides and/or antibodies that inhibit fusion mediated by hepatitis C virus envelope protein 1 is synergistic in preventing or inhibiting HCV infection. 
     
     
         15 . A peptide having the sequence of any one of SEQ ID NO:1-6 or an inhibitory portion thereof. 
     
     
         16 . A peptide consisting of the sequence of any one of SEQ ID NO: 1-6. 
     
     
         17 . A peptide having the sequence of any one of SEQ ID NO:7-42 or an inhibitory portion thereof. 
     
     
         18 . A peptide consisting of the sequence of any one of SEQ ID NO:7-42.