PEPTIDE-BASED INHIBITORS OF THE HEPATITIS-C VIRUS SERINE-PROTEASE

Hexapeptide DDIVPC-OH is a competitive inhibitor of the hepatitis C vi rus (HCV) NS3 protease complexed with NS4A cofactor peptide. This hexa peptide corresponds to the N-terminal cleavage product of an HCV dodec apeptide substrate derived from the NS5A/5B cleavage site. Structure-a ctivity studies on Ac-DDIVPC-OH revealed that side chains of the P4, P 3 and P1 residues contribute the most to binding and that the introduc tion of a D-amino acid at the P5 position improves potency considerabl y. Furthermore, there is a strong preference for cysteine at the P1 po sition and conservative replacements, such as serine, are not well tol erated. (C) 1998 Elsevier Science Ltd. All rights reserved.