抑制丙肝病毒复制的海洋微生物活性物质的筛选及分子机理研究

丙型肝炎是由丙肝病毒HCV引起的一种慢性肝炎，全球约有1.7亿人感染该病毒。临床上目前采用的治疗方法效果并不理想，开发出更安全有效的抗病毒药物已迫在眉睫。随着陆地微生物发现新型抗生素几率的逐渐减少，从海洋微生物中寻找新型抗生素已得到了科学家的认可。本项目一方面将以人体蛋白eIF3及HCV编码蛋白NS3，NS5B为靶位点，高通量筛选能够特异性抑制相应靶位点活性的海洋微生物活性物质。另一方面，以含有绿色荧光蛋白GFP的HCV复制子细胞培养体系为平台，针对未知靶位点筛选能够抑制HCV复制的海洋微生物活性物质。以此为基础，选取有明显抑制效果的活性物质，结合分子遗传学，分子生物学等手段在相应微生物中深入研究该活性物质的产生及调控机制，以及抑制HCV复制的分子机理。以期获得一种或几种有效抑制HCV复制的海洋微生物活性物质，用于将来的抗HCV药物的研发，同时为HCV类似病毒抑制药物的研发提供理论依据。

Hepatitis C Virus (HCV) is the primary pathogen of hepatitis C and approximately 170 million people worldwide are infected with the HCV. The safer and higher effective drugs inhibiting HCV replication are urgently needed because the efficiency of current clinical therapy is not satisfactory. With less novel antibiotics isolated from terrestrial microorganisms, more and more scientists focus on the marine microorganisms to get novel antibiotics. On the one hand,this project is going to high-throughput screen the natural products inhibiting HCV replication from marine microorganisms using the human eIF3 protein and the HCV encoding proteins NS3 and NS5B as the screening targets. On the other hand, the project will also screen the natural products inhibiting HCV replication via unknown targets with the replication system containing the replicon inserted with the GFP. Based on the positive results, we will choose the most effective natural products as the candidates to study their corresponding molecular mechanisms of production, regulation and HCV inhibition via the ways of molecular genetics and molecular biology. We expect to get one or more effective marine natural product(s) inhibiting HCV replication, which will be used as the candidates for the future drug design of HCV. Moreover, these results will provide theoretical basis for the research of drugs inhibiting other HCV-related virus.