HCV Entry: Mechanisms and Therapeutics

 描述（由申请人提供）：尽管出现了针对病毒蛋白酶和RNA聚合酶的特异性抑制剂，但丙型肝炎病毒（HCV）仍然是公共卫生的主要威胁。耐药性的产生，作为直接杀死或抑制病毒生长的治疗剂攻击的自然结果，需要替代的和更强大的治疗剂。我们的实验室一直在研究HCV进入的机制，希望为抗病毒药物的开发确定新的细胞靶点。针对宿主功能的进入抑制剂将是 在治疗移植后丙型肝炎中特别有价值，其中主要未满足的需求之一是开发预防移植后肝移植物再感染的策略。e等人先前证明紧密连接蛋白occludin是一种新的HCV进入因子。在之前的资助期间，我们继续阐明病毒进入细胞所需的其他人为因素，现在已经获得了HCV糖蛋白E2与宿主之间分子相互作用的第一个完整图谱。我们的研究结果表明，两种宿主支架蛋白，抑制素1和2，通过它们与CRaf的相互作用在结合后步骤调节HCV进入。这一成就为剖析HCV进入过程和将基础研究转化为抗病毒药物开发提供了前所未有的机会。在这种竞争性的更新，我们建议解剖的主信号通路，协调HCV进入。我们的研究将首次确定白藜芦醇-CRaf信号通路在HCV进入中的作用，阐明白藜芦醇-CRaf激活所控制的分子事件，并探索靶向白藜芦醇作为阻止HCV感染的方法的可能性。总之，完成该项目将显着推进我们对HCV进入的理解，并可能导致一类新的进入抑制剂。

 DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) remains a major threat to public health despite the advent of specific inhibitors targeting viral protease and RNA polymerase. Resistance development, as a natural outcome from attack by therapeutics that directly kill or inhibit the growth of virus, demands alternative and more powerful therapeutics. Our laboratory has been studying the mechanisms of HCV entry in the hopes of identifying novel cellular targets for antiviral development. Entry inhibitors targeting host functions will be particularly valuable in treating post-transplant hepatitis C, where one of the major unmet needs is the development of strategies to prevent re-infection of the liver graft after transplantation. e and others previously demonstrated that tight junction protein occludin is a novel HCV entry factor. During the previous funding period, we then went on to elucidate additional human factors required for viral entry into cells, and have now acquired the first complete map of the molecular interactions between HCV glycoprotein E2 and the host. Our findings show that two host scaffold proteins, prohibitin 1 and 2, regulate HCV entry at a post- binding step through their interactions with CRaf. This achievement opens unprecedented opportunities to dissect the HCV entry process and to translate basic research into antiviral development. In this competing renewal, we propose to dissect the master signaling pathway that coordinates HCV entry. Our studies will, for the first time, define the role of the prohibitin-CRaf signaling pathway in HCV entry, elucidate the molecular events governed by prohibitin-CRaf activation, and explore the possibility of targeting prohibitins as a way to stop HCV infection. Taken together, accomplishing the project will significantly advance our understanding of HCV entry, and potentially lead to a new class of entry inhibitors.