title: Simultaneously Targeting the NS3 Protease and Helicase Activities for More Effective Hepatitis C Virus Therapy.
abstract: This study examines the specificity and mechanism of action of a recently reported hepatitis C virus (HCV) nonstructural protein 3 (NS3) helicase-protease inhibitor (HPI), and the interaction of HPI with the NS3 protease inhibitors telaprevir, boceprevir, danoprevir, and grazoprevir. HPI most effectively reduced cellular levels of subgenomic genotype 4a replicons, followed by genotypes 3a and 1b replicons. HPI had no effect on HCV genotype 2a or dengue virus replicon levels. Resistance evolved more slowly to HPI than telaprevir, and HPI inhibited telaprevir-resistant replicons. Molecular modeling and analysis of the ability of HPI to inhibit peptide hydrolysis catalyzed by a variety of wildtype and mutant NS3 proteins suggested that HPI forms a bridge between the NS3 RNA-binding cleft and an allosteric site previously shown to bind other protease inhibitors. In most combinations, the antiviral effect of HPI was additive with telaprevir and boceprevir, minor synergy was observed with danoprevir, and modest synergy was observed with grazoprevir.
authors.forename: Jean
authors.initials: J
authors.lastname: Ndjomou
authors.forename: M Josie
authors.initials: MJ
authors.lastname: Corby
authors.forename: Noreena L
authors.initials: NL
authors.lastname: Sweeney
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Hanson
authors.affiliation: ‡Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, United States.
authors.forename: Cihan
authors.initials: C
authors.lastname: Aydin
authors.affiliation: ‡Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, United States.
authors.forename: Akbar
authors.initials: A
authors.lastname: Ali
authors.affiliation: ‡Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, United States.
authors.forename: Celia A
authors.initials: CA
authors.lastname: Schiffer
authors.affiliation: §University of Kansas Specialized Chemistry Center, University of Kansas, 2034 Becker Drive, Lawrence, Kansas 66047, United States.
authors.forename: Kelin
authors.initials: K
authors.lastname: Li
authors.affiliation: §University of Kansas Specialized Chemistry Center, University of Kansas, 2034 Becker Drive, Lawrence, Kansas 66047, United States.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Frankowski
authors.affiliation: §University of Kansas Specialized Chemistry Center, University of Kansas, 2034 Becker Drive, Lawrence, Kansas 66047, United States.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Schoenen
authors.forename: David N
authors.initials: DN
authors.lastname: Frick
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D016174:Hepacivirus / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology; D006801:Humans; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D009842:Oligopeptides / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D009842:Oligopeptides; D011480:Protease 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; C486464:telaprevir