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

被引:2
作者
Zhai, Pei-bin [1 ,2 ,3 ]
Qing, Jie [4 ,5 ]
Li, Ben [3 ]
Zhang, Lin-qi [4 ,5 ]
Ma, Lan [1 ,2 ]
Chen, Li [3 ]
机构
[1] Fudan Univ, Sch Basic Med Sci, Shanghai 200032, Peoples R China
[2] Fudan Univ, Inst Brain Sci, Shanghai 200032, Peoples R China
[3] Ginkgopharma Co Ltd, Suzhou 215123, Peoples R China
[4] Tsinghua Univ, Sch Med, Comprehens AIDS Res Ctr, Beijing 100084, Peoples R China
[5] Tsinghua Univ, Sch Med, Res Ctr Publ Hlth, Beijing 100084, Peoples R China
关键词
HCV; NS3/4A; direct acting antiviral therapy; GP205; sofosbuvir; daclatasvir; GENOTYPE; 1; INFECTION; DIRECT-ACTING ANTIVIRALS; TREATMENT-NAIVE PATIENTS; DACLATASVIR PLUS ASUNAPREVIR; PEGYLATED INTERFERON; PRECLINICAL PROFILE; RANDOMIZED-TRIAL; NULL RESPONDERS; HCV; RIBAVIRIN;
D O I
10.1038/s41401-018-0046-2
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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 clink, 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 lb 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.
引用
收藏
页码:1746 / 1752
页数:7
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