HBV核衣壳蛋白组装成核衣壳是HBV复制的必需环节，利用核衣壳组装抑制剂破坏此环节能够有效阻断病毒复制，此环节已经成为研究抗HBV新药先导化合物的重要靶点。目前核衣壳组装抑制剂的主要问题是：(1) 需要与核衣壳蛋白的结合能力更高并成药性好的新型抑制剂； (2) 尚未阐明抑制剂通过影响核衣壳包装pgRNA，以及干预核衣壳蛋白与宿主蛋白的相互作用，从而抑制HBV复制和潜伏的机制。申请者在前期研究中发现一类新结构骨架的，具有较高破坏核衣壳组装和抗HBV复制活性的化合物。本项目将以此为基础，首先通过构效关系和结合模式研究，设计合成具有更高抑制核衣壳组装活性和抗HBV复制活性，且成药性质优秀的核衣壳组装抑制剂。本项目还将研究抑制剂对核衣壳蛋白磷酸化等翻译后修饰的作用，以及抑制剂干预cccDNA功能的机制。为深入理解核衣壳蛋白的功能，研究治疗乙肝的创新药物提供研究基础和新的思路。

HBV capsid assembly is the indispensable process for viral replication. Inhibition of capsid assembly leads to abruption of viral replication. Thereof, HBV capsid assembly is an important target for anti-HBV new drug. The current problems are: (1) The new inhibitors of novel structure skeleton with higher binding affinity and better drug-like properties are needed. (2) The mechanisms of affecting HBV replication and latency correlating with pgRNA and host proteins need to be elucidated. We discovered that a novel compound strongly interacted with capsid and had potent anti-HBV replication activity. We will apply these discoveries to design and synthesize compounds with better drug-like properties and higher activities to inhibit capsid assembly and HBV replication. We will also study the compounds’ activity to inhibit phosphorylation and other protein post-translational modifications of capsid protein. Meanwhile, the compounds’ influence on the cccDNA functions via host proteins will also be studied. This project will afford research basis to more comprehensively study functions of capsid protein and to discover new anti-hepatitis B lead compounds.