难治性丙肝对干扰素联合利巴韦林和蛋白酶抑制剂治疗不敏感，急需寻找能在丙肝病毒（HCV）生活周期的不同节点上抑制病毒的新靶点。本课题组长期从事抗HCV药物研究，前期筛选了近百种药用植物，从华中五味子果实中分离到2种具有抗HCV活性的四环三萜类化合物-安五酸和甘五酸。前期工作显示：安五酸和甘五酸干扰HCV与细胞受体结合，阻止病毒的细胞入侵，具有显著的抗HCV活性（IC50分别为13.41μg/ml和10.21μg/ml），其作用靶点与目前所有抗HCV药物均不相同，已申请2项国家发明专利。本课题拟在上述基础上，利用我们已有的HCV体外细胞模型、感染动物模型（树鼩）和受体鉴定分析技术，精确定位四环三萜酸与HCV/细胞受体互作的靶点，从病毒配体和细胞受体两个层面及体外体内两个感染模型系统，阐明其抗HCV作用的分子和细胞机制。课题实施将为开发具有自主知识产权的新型抗HCV药物提供理论支撑和实验依据。

Refractory infection of hepatitis C virus (HCV) is resistant to the current standard of care which consists of pegylated interferon alfa in combination with ribavirin and protease inhibitors. Therefore, it is of great necessity to find out the potential key targets to inhibit viral infection at different steps of HCV life cycle. Our group has long been engaged in screening anti-HCV natural products from nearly hundreds of plants. We have isolated two tetracyclic triterpenoid compounds, anwuweizic acid and ganwuweizic acid, and demonstrated their anti-HCV activities. Previous work suggests that both compounds showed strong anti-HCV activities, significantly influencing virus binding to the cellular receptors and blocking HCV cell entry. IC50 of anwuweizic acid and ganwuweizic acid was 13.41μg/ml and 10.21μg/ml，respectively). These two compounds with distinct targets from other antivial drugs have been applied for two state invention patents. Based on the previous work, our project aims to pinpoint the exact target(s) of tetracyclic triterpenoid acids on HCV/cell receptor complexes, using the existing HCV cell models in vitro, infectious animal models(Tupaia) and receptors identification technology. We will also elucidate the molecular and cellular machanisms on their antiviral activities from two aspects of both virus and host cell by HCV infectious model systems both in vitro and in vivo. Our project will provide theoretical foundation and experimental base for development of innovative anti-HCV drugs with self-intellectual property rights.