title: In vitro activity and resistance profile of samatasvir, a novel NS5A replication inhibitor of hepatitis C virus.
abstract: The hepatitis C virus (HCV) nonstructural 5A (NS5A) protein is a clinically validated target for drugs designed to treat chronic HCV infection. This study evaluated the in vitro activity, selectivity, and resistance profile of a novel anti-HCV compound, samatasvir (IDX719), alone and in combination with other antiviral agents. Samatasvir was effective and selective against infectious HCV and replicons, with 50% effective concentrations (EC50s) falling within a tight range of 2 to 24 pM in genotype 1 through 5 replicons and with a 10-fold EC50 shift in the presence of 40% human serum in the genotype 1b replicon. The EC90/EC50 ratio was low (2.6). A 50% cytotoxic concentration (CC50) of >100 μM provided a selectivity index of >5 × 10(7). Resistance selection experiments (with genotype 1a replicons) and testing against replicons bearing site-directed mutations (with genotype 1a and 1b replicons) identified NS5A amino acids 28, 30, 31, 32, and 93 as potential resistance loci, suggesting that samatasvir affects NS5A function. Samatasvir demonstrated an overall additive effect when combined with interferon alfa (IFN-α), ribavirin, representative HCV protease, and nonnucleoside polymerase inhibitors or the nucleotide prodrug IDX184. Samatasvir retained full activity in the presence of HIV and hepatitis B virus (HBV) antivirals and was not cross-resistant with HCV protease, nucleotide, and nonnucleoside polymerase inhibitor classes. Thus, samatasvir is a selective low-picomolar inhibitor of HCV replication in vitro and is a promising candidate for future combination therapies with other direct-acting antiviral drugs in HCV-infected patients.
authors.affiliation: Idenix Pharmaceuticals, Inc., Cambridge, Massachusetts, USA bilello.john@idenix.com.
authors.forename: J P
authors.initials: JP
authors.lastname: Bilello
authors.affiliation: Idenix Pharmaceuticals, Inc., Cambridge, Massachusetts, USA.
authors.forename: L B
authors.initials: LB
authors.lastname: Lallos
authors.affiliation: Idenix Pharmaceuticals, Inc., Cambridge, Massachusetts, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: McCarville
authors.affiliation: Idenix Pharmaceuticals, Inc., Cambridge, Massachusetts, USA.
authors.forename: M
authors.initials: M
authors.lastname: La Colla
authors.affiliation: Idenix Pharmaceuticals, Inc., Cambridge, Massachusetts, USA.
authors.forename: I
authors.initials: I
authors.lastname: Serra
authors.affiliation: Idenix Pharmaceuticals, Inc., Cambridge, Massachusetts, USA.
authors.forename: C
authors.initials: C
authors.lastname: Chapron
authors.affiliation: Idenix Pharmaceuticals, Inc., Cambridge, Massachusetts, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Gillum
authors.affiliation: Idenix Pharmaceuticals, Inc., Cambridge, Massachusetts, USA.
authors.forename: C
authors.initials: C
authors.lastname: Pierra
authors.affiliation: Idenix Pharmaceuticals, Inc., Cambridge, Massachusetts, USA.
authors.forename: D N
authors.initials: DN
authors.lastname: Standring
authors.affiliation: Idenix Pharmaceuticals, Inc., Cambridge, Massachusetts, USA.
authors.forename: M
authors.initials: M
authors.lastname: Seifer
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics; D004357:Drug Synergism; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D005838:Genotype; D006157:Guanosine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D056945:Hep G2 Cells; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D009154:Mutation; D012093:Replicon; D012254:Ribavirin / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D002219:Carbamates; D006157:Guanosine Monophosphate; D016898:Interferon-alpha; D012254:Ribavirin; D017361:Viral Nonstructural Proteins; C557801:IDX184; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C000597389:samatasvir; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase