title: Identification of a lead like inhibitor of the hepatitis C virus non-structural NS2 autoprotease.
abstract: Hepatitis C virus (HCV) non-structural protein 2 (NS2) encodes an autoprotease activity that is essential for virus replication and thus represents an attractive anti-viral target. Recently, we demonstrated that a series of epoxide-based compounds, previously identified as potent inhibitors of the clotting factor, FXIII, also inhibited NS2-mediated proteolysis in vitro and possessed anti-viral activity in cell culture models. This suggested that a selective small molecule inhibitor of the NS2 autoprotease represents a viable prospect. In this independent study, we applied a structure-guided virtual high-throughput screening approach in order to identify a lead-like small molecule inhibitor of the NS2 autoprotease. This screen identified a molecule that was able to inhibit both NS2-mediated proteolysis in vitro and NS2-dependent genome replication in a cell-based assay. A subsequent preliminary structure-activity relationship (SAR) analysis shed light on the nature of the active pharmacophore in this compound and may inform further development into a more potent inhibitor of NS2 mediated proteolysis.
authors.affiliation: School of Chemistry, University of Leeds, Leeds, LS2 9JT, United Kingdom; 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.
authors.forename: Joseph
authors.initials: J
authors.lastname: Shaw
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
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. Electronic address: C.W.G.Fishwick@leeds.ac.uk.
authors.forename: Colin W G
authors.initials: CW
authors.lastname: Fishwick
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006526:Hepatitis C / Q000821:virology*; D006801:Humans; D008958:Models, Molecular; D009842:Oligopeptides / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000187:drug effects / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D015853:Cysteine Proteinase Inhibitors; C097010:NS2 protein, Hepatitis C virus; D009842:Oligopeptides; D054852:Small Molecule Libraries; D017361:Viral Nonstructural Proteins; C486464:telaprevir; D003546:Cysteine Endopeptidases; C107824:NS2-3 protease
keywords: Autoprotease; Hepatitis C virus; NS2; Small molecule inhibitor