title: The hepatitis C virus NS5A inhibitor (BMS-790052) alters the subcellular localization of the NS5A non-structural viral protein.
abstract: The hepatitis C virus (HCV) non-structural (NS) 5A protein plays an essential role in the replication of the viral RNA by the membrane-associated replication complex (RC). Recently, a putative NS5A inhibitor, BMS-790052, exhibited the highest potency of any known anti-HCV compound in inhibiting HCV replication in vitro and showed a promising clinical effect in HCV-infected patients. The precise mechanism of action for this new class of potential anti-HCV therapeutics, however, is still unclear. In order to gain further insight into its mode of action, we sought to test the hypothesis that the antiviral effect of BMS-790052 might be mediated by interfering with the functional assembly of the HCV RC. We observed that BMS-790052 indeed altered the subcellular localization and biochemical fractionation of NS5A. Taken together, our data suggest that NS5A inhibitors such as BMS-790052 can suppress viral genome replication by altering the proper localization of NS5A into functional RCs.
authors.affiliation: Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Choongho
authors.initials: C
authors.lastname: Lee
authors.forename: Han
authors.initials: H
authors.lastname: Ma
authors.forename: Julie Qi
authors.initials: JQ
authors.lastname: Hang
authors.forename: Vincent
authors.initials: V
authors.lastname: Leveque
authors.forename: Ella H
authors.initials: EH
authors.lastname: Sklan
authors.forename: Menashe
authors.initials: M
authors.lastname: Elazar
authors.forename: Klaus
authors.initials: K
authors.lastname: Klumpp
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Glenn
mesh_terms: D000998:Antiviral Agents / Q000378:metabolism*; D002219:Carbamates; D002460:Cell Line; D016174:Hepacivirus / Q000187:drug effects*; D022781:Hepatocytes / Q000821:virology; D006801:Humans; D007093:Imidazoles / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D011759:Pyrrolidines; D014633:Valine / Q000031:analogs & derivatives; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D011759:Pyrrolidines; D014633:Valine; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C549273:daclatasvir