The Second-generation of Highly Potent Hepatitis C Virus (HCV) NS3/4A Protease Inhibitors: Evolutionary Design Based on Tailor-made Amino Acids, Synthesis and Major Features of Bio-activity

Shuni Wang; Yibing Wang; Jiang Wang; Tatsunori Sato; Kunisuke Izawa; Vadim A Soloshonok; Hong Liu

doi:10.2174/1381612823666170522122424

The Second-generation of Highly Potent Hepatitis C Virus (HCV) NS3/4A Protease Inhibitors: Evolutionary Design Based on Tailor-made Amino Acids, Synthesis and Major Features of Bio-activity

Curr Pharm Des. 2017;23(30):4493-4554. doi: 10.2174/1381612823666170522122424.

Authors

Shuni Wang¹, Yibing Wang¹, Jiang Wang¹, Tatsunori Sato², Kunisuke Izawa², Vadim A Soloshonok³, Hong Liu⁴

Affiliations

¹ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
² Hamari Chemicals Ltd., 1-4-29 Kunijima, Higashi-Yodogawa-ku, Osaka 533-0024, Japan.
³ IKERBASQUE, Basque Foundation for Science, Alameda Urquijo 36-5, Plaza Bizkaia, 48011 Bilbao, Spain.
⁴ CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.

PMID: 28530544
DOI: 10.2174/1381612823666170522122424

Abstract

Hepatitis C is a current pandemic liver disease caused by the hepatitis C virus (HCV) with high morbidity and mortality. Recently, the direct-acting antiviral agents (DAAs) targeting HCV NS3/4A, NS5A and NS5B have become the most effective therapies against HCV infection in the clinical treatment. Among them, the second-generation of NS3/4A inhibitors have emerged as the mainstay of the DAA therapies, which are derived from the peptide substrate of NS3/4A protease and modified with various tailor-made amino acids in order to achieve high sustained virologic response (SVR) against HCV. This review summarizes sixteen examples of the second-generation of HCV NS3/4A inhibitors, mainly focusing on the clinical application, structure development, structure-activity relationship (SAR) and their synthesis.

Keywords: Hepatitis C virus (HCV); NS3/4A protease inhibitor; asymmetric synthesis; direct-acting antiviral agents (DAAs); pandemic; ring-closing metathesis (RCM); structure-activity relationship (SAR); tailor-made amino acids.