Article

GP205, a new hepatitis C virus NS3/4A protease inhibitor, displays higher metabolic stability in vitro and drug exposure in vivo

Authors: Pei-bin Zhai1,2, Jie Qing3, Ben Li2, Lin-qi Zhang3, Lan Ma1, Li Chen2
1 School of Basic Medical Sciences and the Institutes of Brain Science, Fudan University, Shanghai 200032, China
2 Ginkgopharma Co. Ltd, Suzhou 215123, China
3 Comprehensive AIDS Research Center and Research Center for Public Health, School of Medicine, Tsinghua University, Beijing 100084, China
Correspondence to: Pei-bin Zhai: 12111010100@fudan.edu.cn, Li Chen: chenli@ginkgopharma.com,
DOI: 10.1038/s41401-018-0046-2
Received: 7 February 2018
Accepted: 12 May 2018
Advance online: 21 June 2018

Abstract

NS3/4A serine protease is a prime target for direct-acting antiviral therapies against hepatitis C virus (HCV) infection. Several NS3/4A inhibitors have been widely used in clinic, while new inhibitors with better characteristics are still urgently needed. GP205 is a new macrocyclic inhibitor of NS3/4A with low nanomolar activities against HCV replicons of genotypes 1b, 2a, 4a, and 5a, with EC50 values ranging from 1.5 to 12.8 nmol/L. In resistance selection study in vitro, we found resistance-associated substitutions on D168: The activity of GP205 was significantly attenuated against 1b replicon with D168V or D168A mutation, similar as simeprevir. No cross resistance of GP205 with NS5B or NS5A inhibitor was observed. Combination of GP205 with sofosbuvir or daclatasvir displayed additive or synergistic efficacy. The pharmacokinetic profile of GP205 was characterized in rats and dogs after oral administration, which revealed good drug exposure both in plasma and in liver and long plasma half-life. The in vitro stability test showed ideal microsomal and hepatic cells stability of GP205. The preclinical profiles of GP205 support further research on this NS3/ 4A inhibitor to expand the existing HCV infection therapies.
Keywords: HCV; NS3/4A; direct acting antiviral therapy; GP205; sofosbuvir; daclatasvir

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