title: Discovery of an allosteric mechanism for the regulation of HCV NS3 protein function.
abstract: Here we report a highly conserved new binding site located at the interface between the protease and helicase domains of the hepatitis C virus (HCV) NS3 protein. Using a chemical lead, identified by fragment screening and structure-guided design, we demonstrate that this site has a regulatory function on the protease activity via an allosteric mechanism. We propose that compounds binding at this allosteric site inhibit the function of the NS3 protein by stabilizing an inactive conformation and thus represent a new class of direct-acting antiviral agents.
authors.affiliation: Astex Pharmaceuticals, Cambridge Science Park, Cambridge, UK.
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Saalau-Bethell
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Woodhead
authors.forename: Gianni
authors.initials: G
authors.lastname: Chessari
authors.forename: Maria G
authors.initials: MG
authors.lastname: Carr
authors.forename: Joseph
authors.initials: J
authors.lastname: Coyle
authors.forename: Brent
authors.initials: B
authors.lastname: Graham
authors.forename: Steven D
authors.initials: SD
authors.lastname: Hiscock
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Murray
authors.forename: Puja
authors.initials: P
authors.lastname: Pathuri
authors.forename: Sharna J
authors.initials: SJ
authors.lastname: Rich
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Richardson
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Williams
authors.forename: Harren
authors.initials: H
authors.lastname: Jhoti
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000495:Allosteric Site / Q000187:drug effects / Q000235:genetics; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D008024:Ligands; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases