title: Quinolones as HCV NS5B polymerase inhibitors.
abstract: Hepatitis C virus (HCV) infection is treated with a combination of peginterferon alfa-2a/b and ribavirin. To address the limitations of this therapy, numerous small molecule agents are in development, which act by directly affecting key steps in the viral life-cycle. Herein we describe our discovery of quinolone derivatives, novel small-molecules that inhibit NS5b polymerase, a key enzyme of the viral life-cycle. A crystal structure of a quinoline analog bound to NS5B reveals that this class of compounds binds to allosteric site-II (non-nucleoside inhibitor-site 2, NNI-2) of this protein.
authors.affiliation: Myriad Pharmaceuticals, 305 Chipeta Way, Salt Lake City, UT 84108, USA.
authors.forename: Dange V
authors.initials: DV
authors.lastname: Kumar
authors.forename: Roopa
authors.initials: R
authors.lastname: Rai
authors.forename: Ken A
authors.initials: KA
authors.lastname: Brameld
authors.forename: John R
authors.initials: JR
authors.lastname: Somoza
authors.forename: Ravi
authors.initials: R
authors.lastname: Rajagopalan
authors.forename: James W
authors.initials: JW
authors.lastname: Janc
authors.forename: Yu M
authors.initials: YM
authors.lastname: Xia
authors.forename: Tony L
authors.initials: TL
authors.lastname: Ton
authors.forename: Michael B
authors.initials: MB
authors.lastname: Shaghafi
authors.forename: Huiyong
authors.initials: H
authors.lastname: Hu
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lehoux
authors.forename: Nhat
authors.initials: N
authors.lastname: To
authors.forename: Wendy B
authors.initials: WB
authors.lastname: Young
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Green
mesh_terms: D000494:Allosteric Regulation; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016174:Hepacivirus / Q000201:enzymology*; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D015363:Quinolones; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase