title: Antiviral activity and resistance of HCV NS5A replication complex inhibitors.
abstract: Treatment of Hepatitis C Virus (HCV) infection is rapidly evolving with the introduction of direct acting antiviral agents (DAA). HCV NS5A replication complex inhibitors, exemplified by Daclatasvir (BMS-790052), represent a new class of DAA. The exceptional in vitro potency (EC50 values at pM to low nM range) and broad genotype coverage of NS5A inhibitors have translated to robust anti-HCV effects in infected patients, making NS5A inhibitors an essential component of effective HCV DAA combination therapies. On the basis of drug-induced resistance substitutions and computer modeling, NS5A inhibitors most likely act at the N-terminus of NS5A (domain I). Mechanism of inhibition studies to elucidate the exquisite potency of these inhibitors have generated several working models.
authors.affiliation: Bristol Myer Squibb Company, Wallingford, CT 06492, United States. Electronic address: min.gao@bms.com.
authors.forename: Min
authors.initials: M
authors.lastname: Gao
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology / Q000235:genetics / Q000502:physiology; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase