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 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.
Llinàs-Brunet
M
M
Bio-Méga Research Division, Boehringer Ingelheim (Canada) Ltd., Laval, Québec, Canada.
Bailey
M
M
Fazal
G
G
Goulet
S
S
Halmos
T
T
Laplante
S
S
Maurice
R
R
Poirier
M
M
Poupart
M A
MA
Thibeault
D
D
Wernic
D
D
Lamarre
D
D
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
D009842:Oligopeptides; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases