Design and synthesis of aminothiazole based Hepatitis B Virus (HBV) capsid inhibitors
Design and synthesis of aminothiazole based Hepatitis B Virus (HBV) capsid inhibitors
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基于氨基噻唑的乙型肝炎病毒（HBV）衣壳抑制剂的设计与合成
DOI：
10.1016/j.ejmech.2019.01.059
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发表时间：
2019-03-15
影响因子：
6.7
通讯作者：
Zhang, Hui
中科院分区：
文献类型：
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作者：
Pan, Ting;Ding, Yanchao;Zhang, Hui
衣壳组装是乙型肝炎病毒（B型肝炎病毒）生命周期的重要步骤，也是抗乙型肝炎病毒药物开发的重要目标。本研究利用高通量筛选技术（HTS）筛选出一个具有氨基噻唑结构的靶化合物，该化合物能抑制HBV衣壳蛋白在细胞内的相互作用。对目标化合物进行了结构跳跃和构效关系研究，结果表明化合物79具有较强的抗HBV复制活性和良好的碱性药物样性质。工作机制研究表明，化合物79可以通过类似的疏水作用，但以不同的氢键与已知的HBV衣壳抑制剂与杂芳基二氢嘧啶（HAP）骨架的类似结合位点结合。该化合物在细胞培养和小鼠体内均对HBV产生产生具有有效的抑制作用，且无明显的急性毒性。我们建议进一步开发这种化合物可能会导致新的有效的抗HBV抑制剂，靶向HBV衣壳组装。(C)2019 Elsevier Masson SAS。All rights reserved.
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. (C) 2019 Elsevier Masson SAS. All rights reserved.