NS5B聚合酶因其在HCV复制中的关键作用，是当前抗HCV药物设计的重要靶点之一。我们前期工作发现了系列结构新颖的C-2β-OH嘧啶酮类化合物，其体外细胞水平抗HCV活性显著优于临床上使用的抗HCV药物利巴韦林，对NS5B聚合酶活性具有明显的抑制作用。本申请以NS5B聚合酶为靶点，基于分子模拟实验的结果，分析了先导物可能的作用机理，并以此为理论指导，采用计算机辅助药物设计的方法在固定其母体结构、保留主要药效团的基础上，拟对先导物嘧啶环C-2、C-5、C-6位进行系统的结构修饰，设计合成系列新型多取代嘧啶酮类NS5B聚合酶抑制剂，并对其进行抗HCV活性和毒性研究，分析作用机制，探讨构效关系，以开发具有我国自主知识产权的优良抗HCV新药候选物。

Because of its key role in HCV replication, RNA-dependent RNA polymerase (NS5B) of HCV is one of the most important targets in developing new HCV infection blocking drugs. Our previous work has indentified a series of novel molecular scaffolds of C-2β-OH pyrimidione analogs able to inhibit NS5B polymerase. These compounds have displayed a higher anti-HCV activity than ribavirin, a current clinical used anti-HCV drug, in a cell-based HCV replica assay. Based on the results of the molecular simulation, we have analyzed the possible mechanism of lead compound with NS5B polymerase by using NS5B polymerase as the target enzyme. In this project, we intend to make systematic structural modification on C-2, C-5, C-6 sites of the pyrimidine ring by using computer aided drug design method (CADD) . We will focus on synthesizing the target molecules and evaluating their anti-HCV activities and cytotoxicity, as well as analyzing the interacting mechanism and discussing the structure relationship of the active compounds. These studies could lead to the development of new anti-HCV drug candidates with Chinese domestic intellectual property.