title: Epoxide based inhibitors of the hepatitis C virus non-structural 2 autoprotease.
abstract: Hepatitis C virus (HCV) non-structural 2 (NS2) encodes an essential protease activity responsible for processing at the NS2-NS3 junction which represents an attractive antiviral target. Attempts to inhibit the NS2 autoprotease with mechanism-based protease inhibitors and substrate peptides have had limited success. We report a series of epoxide-containing small molecules capable of blocking NS2-NS3 proteolysis in vitro and demonstrate the potential for selectivity towards the NS2 autoprotease. A compound within this series was able to perturb HCV genome replication in a subgenomic replicon system only when polyprotein processing was dependent on NS2 autoprotease activity, in addition it inhibited replication of full length HCV. These findings suggest blocking HCV polyprotein processing through inhibition of the NS2 autoprotease represents a viable route to exert an antiviral effect.
authors.affiliation: School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom; School of Chemistry, University of Leeds, Leeds LS2 9JT, United Kingdom; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom.
authors.forename: Joseph
authors.initials: J
authors.lastname: Shaw
authors.affiliation: School of Chemistry, University of Leeds, Leeds LS2 9JT, United Kingdom; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom.
authors.forename: Colin W G
authors.initials: CW
authors.lastname: Fishwick
authors.affiliation: School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom. Electronic address: m.harris@leeds.ac.uk.
authors.forename: Mark
authors.initials: M
authors.lastname: Harris
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004852:Epoxy Compounds / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D011480:Protease Inhibitors / Q000494:pharmacology; D012367:RNA, Viral / Q000235:genetics; D012093:Replicon; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D004852:Epoxy Compounds; C097010:NS2 protein, Hepatitis C virus; D011480:Protease Inhibitors; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; D003546:Cysteine Endopeptidases; C107824:NS2-3 protease
keywords: Autoprotease; Epoxide; Hepatitis C virus; Inhibitor; NS2