title: Peptide-based inhibitors of the hepatitis C virus serine protease.
abstract: 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 D-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.
authors.affiliation: Bio-Méga Research Division, Boehringer Ingelheim (Canada) Ltd., Laval, Québec, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Llinàs-Brunet
authors.forename: M
authors.initials: M
authors.lastname: Bailey
authors.forename: G
authors.initials: G
authors.lastname: Fazal
authors.forename: S
authors.initials: S
authors.lastname: Goulet
authors.forename: T
authors.initials: T
authors.lastname: Halmos
authors.forename: S
authors.initials: S
authors.lastname: Laplante
authors.forename: R
authors.initials: R
authors.lastname: Maurice
authors.forename: M
authors.initials: M
authors.lastname: Poirier
authors.forename: M A
authors.initials: MA
authors.lastname: Poupart
authors.forename: D
authors.initials: D
authors.lastname: Thibeault
authors.forename: D
authors.initials: D
authors.lastname: Wernic
authors.forename: D
authors.initials: D
authors.lastname: Lamarre
mesh_terms: D000595:Amino Acid Sequence; D016174:Hepacivirus / Q000201:enzymology*; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D009842:Oligopeptides; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases