Discovery of novel small molecules targeting hepatitis B virus core protein from marine natural products with HiBiT-based high-throughput screening

作者：Chao Huang, Yang Jin, Panpan Fu, Kongying Hu, Mengxue Wang, Wenjing Zai, Hua Ting, Xinluo Song, Jianyu Ye, Yiqing Zhang, Gan Luo, H L Wang, Jiangxia Liu, Jieliang Chen, Xu‐Wen Li, Zhenghong Yuan · 发表于：Acta Pharmaceutica Sinica B · 年份：2024 · DOI：10.1016/j.apsb.2024.07.019 · 被引用次数：7 · 研究领域：Hepatitis B Virus Studies、Hepatitis C virus research、Bacteriophages and microbial interactions

Due to the limitations of current anti-HBV therapies, the HBV core (HBc) protein assembly modulators (CpAMs) are believed to be potential anti-HBV agents. Therefore, discovering safe and efficient CpAMs is of great value. In this study, we established a HiBiT-based high-throughput screening system targeting HBc and screened novel CpAMs from an in-house marine chemicals library. A novel lead compound 8a, a derivative of the marine natural product naamidine J, has been successfully screened for potential anti-HBV activity. Bioactivity-driven synthesis was then conducted, and the structure‒activity relationship was analyzed, resulting in the discovery of the most effective compound 11a (IC50 = 0.24 μmol/L. Furthermore, 11a was found to significantly inhibit HBV replication in multiple cell models and exhibit a synergistic effect with tenofovir disoproxil fumarate (TDF) and IFNa2 in vitro for anti-HBV activity. Treatment with 11a in a hydrodynamic-injection mouse model demonstrated significant anti-HBV activity without apparent hepatotoxicity. These findings suggest that the naamidine J derivative 11a could be used as the HBV core protein assembly modulator to develop safe and effective anti-HBV therapies.