Resistance Analysis and Characterization of a Thiazole Analogue, BP008, as a Potent Hepatitis C Virus NS5A Inhibitor

• DOI: 10.1128/aac.00599-11
• Publication Date: 2011-10-18T05:22:42Z
• Authors: Hui-Mei Lin; Jing-Chyi Wang; Han-Shu Hu; Pei-Shan Wu; Chi-Chen Yang; Chung-Pu Wu; Szu-Yuan Pu; Tsu-An Hsu; Weir-Torn Jiaang; Yu-Sheng Chao; Jyh-Haur Chern; Teng-Kuang Yeh; Andrew Yueh
• Keywords: NS5A; Replicon; NS5B; NS3; Protease inhibitor (pharmacology)

ABSTRACT Hepatitis C virus (HCV) is a global health problem, affecting approximately 3% of the world's population. The standard treatment for HCV infection often poorly tolerated and ineffective. Therefore, development novel or more effective strategies to treat chronic urgently needed. In this report, BP008, potent small-molecule inhibitor replication, was developed from class compounds with thiazol core structures by means utilizing cell-based replicon system. compound reduced reporter expression HCV1b 50% concentration (EC 50 ) selective index value 4.1 ± 0.7 nM >12,195, respectively. Sequencing analyses several individual clones derived BP008-resistant RNAs purified cells harboring revealed that amino acid substitutions mainly within N-terminal region (domain I) NS5A were associated decreased susceptibility. Q24L, P58S, Y93H are key resistance selection; F149L V153M play compensatory role in replication drug processes. Moreover, BP008 displayed synergistic effects alpha interferon (IFN-α), NS3 protease inhibitor, NS5B polymerase as well good oral bioavailability SD rats favorable exposure rat liver. summary, our results pointed an potentially targets NS5A. can be considered part therapeutic strategy future.