title: An NS3 serine protease inhibitor abrogates replication of subgenomic hepatitis C virus RNA.
abstract: The hepatitis C virus (HCV) NS3 protease is essential for polyprotein maturation and viral propagation, and it has been proposed as a suitable target for antiviral drug discovery. An N-terminal hexapeptide cleavage product of a dodecapeptide substrate identified as a weak competitive inhibitor of the NS3 protease activity was optimized to a potent and highly specific inhibitor of the enzyme. The effect of this potent NS3 protease inhibitor was evaluated on replication of subgenomic HCV RNA and compared with interferon-alpha (IFN-alpha), which is currently used in the treatment of HCV-infected patients. Treatment of replicon-containing cells with the NS3 protease inhibitor or IFN-alpha showed a dose-dependent decrease in subgenomic HCV RNA that reached undetectable levels following a 14-day treatment. Kinetic studies in the presence of either NS3 protease inhibitor or IFN-alpha also revealed similar profiles in HCV RNA decay with half-lives of 11 and 14 h, respectively. The finding that an antiviral specifically targeting the NS3 protease activity inhibits HCV RNA replication further validates the NS3 enzyme as a prime target for drug discovery and supports the development of NS3 protease inhibitors as a novel therapeutic approach for HCV infection.
authors.affiliation: Department of Biological Sciences, Boehringer Ingelheim (Canada) Ltd., Research and Development, Laval, Québec H7S 2G5, Canada.
authors.forename: Arnim
authors.initials: A
authors.lastname: Pause
authors.forename: George
authors.initials: G
authors.lastname: Kukolj
authors.forename: Murray
authors.initials: M
authors.lastname: Bailey
authors.forename: Martine
authors.initials: M
authors.lastname: Brault
authors.forename: Florence
authors.initials: F
authors.lastname: Dô
authors.forename: Ted
authors.initials: T
authors.lastname: Halmos
authors.forename: Lisette
authors.initials: L
authors.lastname: Lagacé
authors.forename: Roger
authors.initials: R
authors.lastname: Maurice
authors.forename: Martin
authors.initials: M
authors.lastname: Marquis
authors.forename: Ginette
authors.initials: G
authors.lastname: McKercher
authors.forename: Charles
authors.initials: C
authors.lastname: Pellerin
authors.forename: Louise
authors.initials: L
authors.lastname: Pilote
authors.forename: Diane
authors.initials: D
authors.lastname: Thibeault
authors.forename: Daniel
authors.initials: D
authors.lastname: Lamarre
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology / Q000627:therapeutic use; D012367:RNA, Viral / Q000096:biosynthesis / Q000187:drug effects*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D012367:RNA, Viral; D015842:Serine Proteinase Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases