Identification of Compounds Targeting Hepatitis B Virus Core Protein Dimerization through a Split Luciferase Complementation Assay
Identification of Compounds Targeting Hepatitis B Virus Core Protein Dimerization through a Split Luciferase Complementation Assay
复制标题
通过裂解荧光素酶互补测定鉴定针对乙型肝炎病毒核心蛋白二聚化的化合物
DOI：
10.1128/aac.01302-18
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发表时间：
2018-12-01
影响因子：
4.9
通讯作者：
Hu, Jie-Li
中科院分区：
文献类型：
--
作者：
Wei, Xia-Fei;Gan, Chun-Yang;Hu, Jie-Li
B型肝炎病毒的衣壳是开发抗慢性B型肝炎感染的疗法的有吸引力的抗病毒靶点。目前可用的核心蛋白变构调节剂（CpAMs）主要影响衣壳组装过程中涉及的两种主要类型的蛋白质-蛋白质相互作用之一，即核心二聚体之间的相互作用。由于缺乏筛选模型，靶向两个核心单体之间相互作用的化合物尚未被严格筛选。我们在这里报告了一种基于细胞的测定，其中核心二聚体的形成通过分裂荧光素酶互补（SLC）来指示。利用该模型，从含有672个化合物的库中鉴定出2个化合物，阿比朵尔（umifenovir）和20-脱氧巨大戟二萜醇，作为核心二聚化调节剂。阿比朵尔和20-脱氧巨大戟二萜醇在体外分别通过减少和增加核心二聚体和衣壳的形成来抑制B病毒（HBV）DNA的复制。我们的研究结果提供了一个概念的细胞模型，用于筛选新的药物靶向核心二聚体和衣壳形成的步骤。
The capsid of the hepatitis B virus is an attractive antiviral target for developing therapies against chronic hepatitis B infection. Currently available core protein allosteric modulators (CpAMs) mainly affect one of the two major types of protein-protein interactions involved in the process of capsid assembly, namely, the interaction between the core dimers. Compounds targeting the interaction between two core monomers have not been rigorously screened due to the lack of screening models. We report here a cell-based assay in which the formation of core dimers is indicated by split luciferase complementation (SLC). Making use of this model, 2 compounds, Arbidol (umifenovir) and 20-deoxyingenol, were identified from a library containing 672 compounds as core dimerization regulators. Arbidol and 20-deoxyingenol inhibit the hepatitis B virus (HBV) DNA replication in vitro by decreasing and increasing the formation of core dimer and capsid, respectively. Our results provided a proof of concept for the cell model to be used to screen new agents targeting the step of core dimer and capsid formation.