Structure-Based Discovery of N-Sulfonylpiperidine-3-carboxamides as Novel Capsid Assembly Modulators for Potent Inhibition of HBV Replication

Abstract

As a key element during HBV replication, a nucleocapsid is considered a promising target for the treatment of chronic hepatitis B. The present study aimed to identify small molecules as novel capsid assembly modulators with antiviral activity. Structure-based virtual screening of an integrated compound library led to the identification of several types of HBV inhibitors. Among these inhibitors, N-sulfonylpiperidine-3-carboxamides (SPCs) potently reduced the amount of secreted HBV DNA. Through structure–activity relationship studies, we identified an SPC derivative, namely, C-39, which exhibited the highest antiviral activity without causing cytotoxicity. Mechanism studies showed that C-39 dose-dependently inhibited the formation of HBV capsid, synthesis of cccDNA, e antigen (HBeAg), viral pregenomic RNA (pgRNA), and HBV DNA levels, thereby restraining HBV replication. In summary, SPCs represent a new class of capsid assembly modulators. Further optimization of SPCs is expected to obtain new antiviral drugs against HBV infection.

Keywords: hepatitis B virus; core protein; capsid; assembly modulator; antiviral activity

关键词：乙型肝炎病毒;  核心蛋白； 核衣壳； 组装抑制剂； 抗病毒活性

Full text: https://www.mdpi.com/1999-4915/14/2/348  

 HBV核衣壳抑制剂筛选流程 

 Yang Yang（杨泱）, Yu Yan（严宇）, Jiaxin Yin, Jie Hu, Xuefei Cai, Jieli Hu, Jie Xia, Kai Wang, Ni Tang, and Luyi Huang. 2022. "Structure-Based Discovery of N-Sulfonylpiperidine-3-carboxamides as Novel Capsid Assembly Modulators for Potent Inhibition of HBV Replication" Viruses 14, no. 2: 348. https://doi.org/10.3390/v14020348