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Inhibition of Hepatitis C Virus replication by GS-6620, a potent C-nucleoside monophosphate prodrug

Feng, JY and Cheng, G and Perry, J and Barauskas, O and Xu, Y and Fenaux, M and Eng, S and Tirunagari, N and Peng, B and Yu, M and Tian, Y and Lee, Y and Stepan, G and Lagpacan, LL and Jin, D and Hung, M and Ku, KS and Han, B and Kitrinos, K and Perron, M and Birkus, G and Wong, KA and Zhong, W and Kim, CU and Carey, A and Cho, A and Ray, AS (2014) Inhibition of Hepatitis C Virus replication by GS-6620, a potent C-nucleoside monophosphate prodrug. Antimicrobial Agents and Chemotherapy. pp. 1930-1942.

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 [EC<sub>50</sub>], 0.048 to 0.68 muM). GS-6620 showed limited activities against other viruses, maintaining only some of its activity against the closely related bovine viral diarrhea virus (EC<sub>50</sub>, 1.5 muM). 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 K <sub>i</sub>/K<sub>m</sub> 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. Copyright 2014, American Society for Microbiology. All Rights Reserved

Item Type: Article
Additional Information: NIBR author: Fenaux, M institute: NIBR- address only contributor address: (Feng, Cheng, Perry, Barauskas, Xu, Fenaux, Eng, Tirunagari, Peng, Yu, Tian, Lee, Stepan, Lagpacan, Jin, Hung, Ku, Han, Kitrinos, Perron, Birkus, Wong, Zhong, Kim, Carey, Cho, Ray) Gilead Sciences, Foster City, CA, United States (Fenaux, Wong, Zhong) Novartis Institute for BioMedical Research, Emeryville, CA, United States (Kim) Kainos Medicine, Asan Institute for Life Sciences, Songpa-gu, Seoul, South Korea
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/22642

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