title: Inhibition of hepatitis C virus replication by GS-6620, a potent C-nucleoside monophosphate prodrug.
abstract: As a class, nucleotide inhibitors (NIs) of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase offer advantages over other direct-acting antivirals, including properties, such as pangenotype activity, a high barrier to resistance, and reduced potential for drug-drug interactions. We studied the in vitro pharmacology of a novel C-nucleoside adenosine analog monophosphate prodrug, GS-6620. It was found to be a potent and selective HCV inhibitor against HCV replicons of genotypes 1 to 6 and against an infectious genotype 2a virus (50% effective concentration [EC50], 0.048 to 0.68 μM). GS-6620 showed limited activities against other viruses, maintaining only some of its activity against the closely related bovine viral diarrhea virus (EC50, 1.5 μM). The active 5'-triphosphate metabolite of GS-6620 is a chain terminator of viral RNA synthesis and a competitive inhibitor of NS5B-catalyzed ATP incorporation, with Ki/Km values of 0.23 and 0.18 for HCV NS5B genotypes 1b and 2a, respectively. With its unique dual substitutions of 1'-CN and 2'-C-Me on the ribose ring, the active triphosphate metabolite was found to have enhanced selectivity for the HCV NS5B polymerase over host RNA polymerases. GS-6620 demonstrated a high barrier to resistance in vitro. Prolonged passaging resulted in the selection of the S282T mutation in NS5B that was found to be resistant in both cellular and enzymatic assays (>30-fold). Consistent with its in vitro profile, GS-6620 exhibited the potential for potent anti-HCV activity in a proof-of-concept clinical trial, but its utility was limited by the requirement of high dose levels and pharmacokinetic and pharmacodynamic variability.
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Joy Y
authors.initials: JY
authors.lastname: Feng
authors.forename: Guofeng
authors.initials: G
authors.lastname: Cheng
authors.forename: Jason
authors.initials: J
authors.lastname: Perry
authors.forename: Ona
authors.initials: O
authors.lastname: Barauskas
authors.forename: Yili
authors.initials: Y
authors.lastname: Xu
authors.forename: Martijn
authors.initials: M
authors.lastname: Fenaux
authors.forename: Stacey
authors.initials: S
authors.lastname: Eng
authors.forename: Neeraj
authors.initials: N
authors.lastname: Tirunagari
authors.forename: Betty
authors.initials: B
authors.lastname: Peng
authors.forename: Mei
authors.initials: M
authors.lastname: Yu
authors.forename: Yang
authors.initials: Y
authors.lastname: Tian
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Lee
authors.forename: George
authors.initials: G
authors.lastname: Stepan
authors.forename: Leanna L
authors.initials: LL
authors.lastname: Lagpacan
authors.forename: Debi
authors.initials: D
authors.lastname: Jin
authors.forename: Magdeleine
authors.initials: M
authors.lastname: Hung
authors.forename: Karin S
authors.initials: KS
authors.lastname: Ku
authors.forename: Bin
authors.initials: B
authors.lastname: Han
authors.forename: Kathryn
authors.initials: K
authors.lastname: Kitrinos
authors.forename: Michel
authors.initials: M
authors.lastname: Perron
authors.forename: Gabriel
authors.initials: G
authors.lastname: Birkus
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Wong
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhong
authors.forename: Choung U
authors.initials: CU
authors.lastname: Kim
authors.forename: Anne
authors.initials: A
authors.lastname: Carey
authors.forename: Aesop
authors.initials: A
authors.lastname: Cho
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Ray
mesh_terms: D000998:Antiviral Agents / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D056945:Hep G2 Cells; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D009705:Nucleosides / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*; D011355:Prodrugs / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D009705:Nucleosides; D011355:Prodrugs; D017361:Viral Nonstructural Proteins