Institute of Human Virology, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China; Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China; Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
Institute of Human Virology, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China; Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China; Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
Eur J Med Chem. 2019 Mar 15;166:480-501. doi: 10.1016/j.ejmech.2019.01.059. Epub 2019 Feb 5.
The capsid assembly is an essential step for Hepatitis B Virus (HBV) life cycle and is an important target for anti-HBV drug development. In this report, we identified a hit compound with aminothiazole structure by the high throughput screening (HTS) which inhibited the interaction of HBV capsid protein within the cells. The structure hopping and SAR studies of the hit compound afforded compound 79 with potent anti-HBV replication activity and good basic drug-like properties. The working mechanism studies showed that compound 79 could bind to the similar binding site of known HBV capsid inhibitor with heteroaryldihydropyrimidine (HAP) scaffold, through similar hydrophobic interactions but with a different hydrogen bond. This compound exerted potent inhibitory effect upon HBV production, either in cell culture or in mice with no obvious acute toxicity. We propose that further development of this compound could lead to novel potent anti-HBV inhibitors that target HBV capsid assembly.
衣壳组装是乙型肝炎病毒（HBV）生命周期的一个重要步骤，也是抗 HBV 药物开发的重要靶点。在本报告中，我们通过高通量筛选（HTS）鉴定出一种具有氨基噻唑结构的命中化合物，该化合物能抑制细胞内 HBV 衣壳蛋白的相互作用。通过对命中化合物的结构跳跃和 SAR 研究，得到了具有较强抗 HBV 复制活性和良好碱性药物样性质的化合物 79。作用机制研究表明，化合物 79 可通过类似的疏水相互作用与已知的 HBV 衣壳抑制剂（杂芳基二氢嘧啶（HAP）骨架）结合在类似的结合位点上，但氢键不同。该化合物对细胞培养或小鼠中的 HBV 产生均具有很强的抑制作用，且无明显的急性毒性。我们提出，进一步开发这种化合物可能会产生针对 HBV 衣壳组装的新型有效抗 HBV 抑制剂。
