title: In VitroAntiviral Activity and Resistance Profile of the Next-Generation Hepatitis C Virus NS5A Inhibitor Pibrentasvir.
abstract: Pibrentasvir (ABT-530) is a novel and pan-genotypic hepatitis C virus (HCV) NS5A inhibitor with 50% effective concentration (EC50) values ranging from 1.4 to 5.0 pM against HCV replicons containing NS5A from genotypes 1 to 6. Pibrentasvir demonstrated similar activity against a panel of chimeric replicons containing HCV NS5A of genotypes 1 to 6 from clinical samples. Resistance selection studies were conducted using HCV replicon cells with NS5A from genotype 1a, 1b, 2a, 2b, 3a, 4a, 5a, or 6a at a concentration of pibrentasvir that was 10- or 100-fold over its EC50for the respective replicon. With pibrentasvir at 10-fold over the respective EC50, only a small number of colonies (0.00015 to 0.0065% of input cells) with resistance-associated amino acid substitutions were selected in replicons containing genotype 1a, 2a, or 3a NS5A, and no viable colonies were selected in replicons containing NS5A from other genotypes. With pibrentasvir at 100-fold over the respective EC50, very few colonies (0.0002% of input cells) were selected by pibrentasvir in genotype 1a replicon cells while no colonies were selected in other replicons. Pibrentasvir is active against common resistance-conferring substitutions in HCV genotypes 1 to 6 that were identified for other NS5A inhibitors, including those at key amino acid positions 28, 30, 31, or 93. The combination of pibrentasvir with HCV inhibitors of other classes produced synergistic inhibition of HCV replication. In summary, pibrentasvir is a next-generation HCV NS5A inhibitor with potent and pan-genotypic activity, and it maintains activity against common amino acid substitutions of HCV genotypes 1 to 6 that are known to confer resistance to currently approved NS5A inhibitors.
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA teresa.ng@abbvie.com.
authors.forename: Teresa I
authors.initials: TI
authors.lastname: Ng
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Preethi
authors.initials: P
authors.lastname: Krishnan
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Tami
authors.initials: T
authors.lastname: Pilot-Matias
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Warren
authors.initials: W
authors.lastname: Kati
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Gretja
authors.initials: G
authors.lastname: Schnell
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Beyer
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Reisch
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Liangjun
authors.initials: L
authors.lastname: Lu
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Dekhtyar
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Irvin
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Tripathi
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Clarence
authors.initials: C
authors.lastname: Maring
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Randolph
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Rolf
authors.initials: R
authors.lastname: Wagner
authors.affiliation: AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Collins
mesh_terms: D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000009:adverse effects* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D024882:Drug Resistance, Viral; D056945:Hep G2 Cells; D016174:Hepacivirus / Q000145:classification / Q000187:drug effects* / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy; D006801:Humans; D011759:Pyrrolidines / Q000009:adverse effects / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D011759:Pyrrolidines; D017361:Viral Nonstructural Proteins; C000622691:pibrentasvir; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: ABT-530; HCV; NS5A inhibitor; antiviral activity; pibrentasvir; resistance