Hepatitis C virus NS5A protein and lipid droplets

描述（由申请人提供）： 丙型肝炎病毒（HCV）是美国和世界许多其他地区慢性肝炎、肝硬化和肝细胞癌的主要原因。目前可用的治疗对许多患者无效。吸毒和酗酒者尤其危险。酒精性肝病患者中有很高比例（高达~ 40%）显示出活动性HCV感染的证据。这些人的预后比没有酗酒的感染者明显更差，因为他们表现出更多的肝功能障碍，肝脏病理学增加和肝纤维化加速。许多研究还表明，病毒复制和肝细胞癌的水平增加，对治疗干预的反应率降低。因此，迫切需要新型药物来阻断酗酒感染者中HCV的复制。寻找新药靶点的一种方法是寻找病毒生命周期所必需的特定病毒-宿主相互作用。由于脂肪肝在酒精性肝病和慢性丙型肝炎中都很常见，我们集中研究HCV蛋白和脂滴之间的关系。已知HCV核心蛋白部分定位于脂滴表面。另一个研究小组最近发现，NS 5A蛋白也定位于脂滴。这一发现已在我们的实验室得到独立证实。我们还绘制了NS 5A蛋白的一个区域，该区域可以介导异源蛋白定位于脂滴，并发现了与NS 5A蛋白的该区域结合的细胞脂滴蛋白。所提出的实验将检验这样的假设，即这种细胞蛋白介导NS 5A蛋白定位于脂滴，并且NS 5A蛋白与这种蛋白和脂滴的结合是高水平HCV RNA复制所必需的。我们还将建立一个快速筛选系统，以寻找可以破坏NS 5A蛋白与细胞蛋白之间相互作用的小分子。预计这些跨学科实验将导致发现用于阻断HCV复制的新型治疗剂，特别是对于脂肪变性患者。

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) is a major cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma in the US and in many other parts of the world. Currently available therapy is not effective in many patients. Drug and alcohol abusers are especially at risk. A high percentage (up to -40%) of people with alcoholic liver disease show evidence of active infection by HCV. The prognosis for these people is significantly worse than for infected people without alcohol abuse, in that they show more hepatic dysfunction, increased hepatic pathology, and accelerated rates of liver fibrosis. Many studies also show increased levels of viral replication and hepatocellular carcinoma and lower response rate to therapeutic intervention. Therefore, there is an urgent need for novel drugs to block HCV replication in infected people who abuse alcohol. One approach to finding new drug targets is to look for specific virus-host interactions that are necessary for the viral life cycle. We are concentrating on the relationship between HCV proteins and lipid droplets, since hepatic steatosis is common in both alcoholic liver disease and chronic hepatitis C. HCV core protein is known to localize, in part, to the surface of lipid droplets. Another group has recently found that the NS5A protein is also localized to lipid droplets. This finding has been independently confirmed in our laboratory. We have also mapped a region of NS5A protein that can mediate the localization of heterelogous proteins to lipid droplets, and found a cellular lipid droplet protein that binds to this region of NS5A protein. The proposed experiments will test the hypothesis that this cellular protein mediates the localization of NS5A protein to lipid droplets, and that the binding of NS5A protein to this protein and lipid droplets is necessary for high-level HCV RNA replication. We will also set up a rapid screening system to look for small molecules that can disrupt the interaction between NS5A protein and the cellular protein. It is anticipated that these interdisciplinary experiments will lead to the discovery of novel therapeutic agents for blocking HCV replication, especially for people with steatosis.