Function and mechanism of the HCV p7 channel and its therapeutic potential

描述(由申请人提供)：这项建议旨在利用结构和功能相结合的方法研究丙型肝炎病毒(丙型肝炎病毒)的病毒孔蛋白p7的功能和治疗潜力。丙型肝炎病毒基因组编码的p7蛋白是病毒复制所必需的；它已被证明有助于有效地组装和释放感染性病毒粒子。在膜上，p7形成阳离子选择性通道。我们实验室最近破解的p7通道的结构显示了由病毒开发的一种新的结构，以跨膜传导阳离子。该结构还揭示了与已知的钙/镁通道部分相似的通道元件，这为进一步研究了解通道机制提供了线索。像大多数病毒孔蛋白一样，p7介导的阳离子传导在病毒组装和释放过程中的功能仍然难以捉摸。P7形成明确的通道结构的事实表明离子通透性在这些过程中的作用，并促使新的研究更好地定义这一作用。P7通道也一直被用作抗丙型肝炎病毒的靶点，因为阻断该通道的活动减少了传染性病毒后代的产生。几种化合物已经被证明可以抑制通道活性，包括金刚烷衍生物，它也可以阻断流感M2通道。这些药物相互作用可能为合理的药物开发提供有用的信息，但这些化合物如何以及在哪里作用于p7通道尚不清楚。我们建议利用生物物理学、分子病毒学和药物化学的多学科方法来研究阳离子传导的机制，通道活性在病毒组装和释放中的作用，以及已知的抑制剂抑制通道的结构基础。从拟议的研究中获得的知识可能会为开发治疗丙型肝炎病毒感染的化合物带来新的机会。

DESCRIPTION (provided by applicant): This proposal aims to investigate the function and therapeutic potential of the viroporin protein, p7, of Hepatitis C virus (HCV) using a combination of structural and functional approaches. The p7 protein encoded by the HCV genome is required for viral replication; it has been shown to facilitate efficient assembly and release of infectious virions. In membrane, p7 forms a cation-selective channel. The structure of the p7 channel solved recently in our lab shows a novel architecture developed by the virus to conduct cations across the membrane. The structure also revealed channel elements that partially resemble those of known Ca2+/Mg2+ channels, which provide clues for further research to understand channel mechanism. Like most viroporins, the function of p7-mediated cation conduction during viral assemble and release remains elusive. The fact that p7 forms a well-defined channel structure suggests a role of ion permeability in these processes, and urges new investigations to better define this role. The p7 channel has also been pursued as an anti-HCV target because blocking the channel activity reduced production of infectious viral progeny. Several compounds have already been shown to inhibit channel activity, including the adamantane derivatives that also block the influenza M2 channel. These drug interactions could provide useful information for rational drug development, but how and where do these compounds act on the p7 channel are unknown. We propose to employ multidisciplinary approaches in biophysics, molecular virology, and medicinal chemistry to investigate the mechanism of cation conduction, the effect of channel activity in virus assembly and release, and the structural bases of channel inhibition by the known inhibitors. The knowledge to be gained from the proposed research may give rise to new opportunities for developing compounds for treating HCV infections.