3C蛋白调控肠道病毒属病毒基因组复制的分子机制研究与相应抑制剂筛选

3C蛋白催化肠道病毒属病毒多蛋白前体的切割和宿主蛋白的降解，一直是抗病毒药物研发的焦点。然而，3C蛋白酶活性中心的亲核性质使得靶向3C蛋白酶活功能的药物研发工作难以推进。在前期工作中，我们发现了3C蛋白上两个全新的、独立于其酶活性中心的可靶向位点，同时首次证明了3C蛋白调控病毒基因组复制的功能是其蛋白酶活性之外的又一药物靶点。本申请项目拟在我们上述前期研究工作基础上展开：一方面，将进一步阐释3C蛋白调控病毒基因组复制的详细分子机制，为针对3C蛋白这一新型调控功能的药物研发工作提供理论依据；另一方面，将针对上述两个全新的靶向位点开展基于DNA编码化合物库的小分子化合物前体筛选工作及初步药效评价。我们期望该研究工作将为抗肠道病毒属病毒的药物研发提供新思路和新靶标。

The 3C protein of Enterovirus has long been the focus of antivirals development. Despite its critical role in viral polyprotein processing, the nucleophilic active site of 3C has frustrated drug discovery efforts. Previously, we identified two novel sites of therapeutic vulnerabilities on 3C, both of which are distinct from its known protease active center. Here, we propose to utilize the DNA-encoded library technology for antivirals development against these two new target sites. Meanwhile, our previous work also showed for the first time that the role 3C played in Enterovirus genome replication is another drug-targetable function besides its protease activity. To provide important framework for future antivirals development against this unexplored function of 3C, we also propose to investigate the detailed molecular mechanism underlying the regulatory role of 3C in Enterovirus replication. We anticipate that this study will shed new lights on the prevention and treatment of enterovirus-related infections.