title: In Vitro Antiviral Activity and Resistance Profile Characterization of the Hepatitis C Virus NS5A Inhibitor Ledipasvir.
abstract: Ledipasvir (LDV; GS-5885), a component of Harvoni (a fixed-dose combination of LDV with sofosbuvir [SOF]), is approved to treat chronic hepatitis C virus (HCV) infection. Here, we report key preclinical antiviral properties of LDV, including in vitro potency, in vitro resistance profile, and activity in combination with other anti-HCV agents. LDV has picomolar antiviral activity against genotype 1a and genotype 1b replicons with 50% effective concentration (EC50) values of 0.031 nM and 0.004 nM, respectively. LDV is also active against HCV genotypes 4a, 4d, 5a, and 6a with EC50 values of 0.11 to 1.1 nM. LDV has relatively less in vitro antiviral activity against genotypes 2a, 2b, 3a, and 6e, with EC50 values of 16 to 530 nM. In vitro resistance selection with LDV identified the single Y93H and Q30E resistance-associated variants (RAVs) in the NS5A gene; these RAVs were also observed in patients after a 3-day monotherapy treatment. In vitro antiviral combination studies indicate that LDV has additive to moderately synergistic antiviral activity when combined with other classes of HCV direct-acting antiviral (DAA) agents, including NS3/4A protease inhibitors and the nucleotide NS5B polymerase inhibitor SOF. Furthermore, LDV is active against known NS3 protease and NS5B polymerase inhibitor RAVs with EC50 values equivalent to those for the wild type.
authors.affiliation: Gilead Sciences, Foster City, California, USA guofeng.cheng@gilead.com.
authors.forename: Guofeng
authors.initials: G
authors.lastname: Cheng
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Doehle
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Betty
authors.initials: B
authors.lastname: Peng
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Amoreena
authors.initials: A
authors.lastname: Corsa
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Ruoyu
authors.initials: R
authors.lastname: Gong
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Yu
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Han
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Simin
authors.initials: S
authors.lastname: Xu
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Hadas
authors.initials: H
authors.lastname: Dvory-Sobol
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Michel
authors.initials: M
authors.lastname: Perron
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Yili
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Mo
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Nikos
authors.initials: N
authors.lastname: Pagratis
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: John O
authors.initials: JO
authors.lastname: Link
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: William
authors.initials: W
authors.lastname: Delaney
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D004338:Drug Combinations; D024882:Drug Resistance, Viral / Q000235:genetics; D004357:Drug Synergism; D005449:Fluorenes / Q000494:pharmacology*; D005838:Genotype; D006367:HeLa Cells; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008826:Microbial Sensitivity Tests; D000069474:Sofosbuvir / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; 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; D002352:Carrier Proteins; D004338:Drug Combinations; D005449:Fluorenes; D047908:Intracellular Signaling Peptides and Proteins; D000069474:Sofosbuvir; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus; C586541:ledipasvir; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
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