title: Highly potent and selective peptide-based inhibitors of the hepatitis C virus serine protease: towards smaller inhibitors.
abstract: Structure-activity studies on a hexapeptide N-terminal cleavage product of a dodecamer substrate led to the identification of very potent and highly specific inhibitors of the HCV NS3 protease/NS4A cofactor peptide complex. The largest increase in potency was accomplished by the introduction of a (4R)-naphthalen-1-yl-4-methoxy substituent to the P2 proline. N-Terminal truncation resulted in tetrapeptides containing a C-terminal carboxylic acid, which exhibited low micromolar activity against the HCV serine protease.
authors.affiliation: Boehringer Ingelheim, Canada Ltd, Research and Development, Laval, Quebec. mllinas@lav.boehringer-ingelheim.com
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: E
authors.initials: E
authors.lastname: Ghiro
authors.forename: V
authors.initials: V
authors.lastname: Gorys
authors.forename: S
authors.initials: S
authors.lastname: Goulet
authors.forename: T
authors.initials: T
authors.lastname: Halmos
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: J
authors.initials: J
authors.lastname: Rancourt
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: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D002918:Chymotrypsin / Q000037:antagonists & inhibitors; D015195:Drug Design; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D007700:Kinetics; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors; D008958:Models, Molecular; D008968:Molecular Conformation; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors; D011487:Protein Conformation; D012697:Serine Endopeptidases / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013552:Swine; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D002401:Cathepsin B; D002918:Chymotrypsin; D019272:Leukocyte Elastase; D009842:Oligopeptides; D010196:Pancreatic Elastase; D012697:Serine Endopeptidases; D015842:Serine Proteinase Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C093542:NS4 protein, hepatitis C virus