Peptide-based inhibitors of the hepatitis C virus serine protease

Hexapeptide DDIVPC-OH is a competitive inhibitor of the hepatitis C virus (HCV) NS3 protease complexed with NS4A cofactor peptide. This hexapeptide corresponds to the N-terminal cleavage product of an HCV dodecapeptide substrate derived from the NS5A/5B cleavage site. Structure-activity studies on Ac-DDIVPC-OH revealed that side chains of the P4, P3 and P1 residues contribute the most to binding and that the introduction of a -amino acid at the P5 position improves potency considerably. Furthermore, there is a strong preference for cysteine at the P1 position and conservative replacements, such as serine, are not well tolerated. Hexapeptide DDIVPC-OH, corresponding to the N-terminal cleavage product of a substrate derived peptide, inhibits the NS3 protease complexed with the NS4A cofactor peptide. Structure-activity studies on this N-terminal product peptide led to Ac-DdIVPC-OH, a competitive inhibitor of the enzyme with a Ki app of 0.6 μM.