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

HCV p7通道的功能、机制及其治疗潜力

基本信息

批准号：
8880443
负责人：
JAMES Jeiwen CHOU
金额：
$ 50.76万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-15 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8880443
关键词：
Adamantane Address Affect Architecture Binding Binding Sites Biological Assay Biophysics Capsid Cations Cells Communities Complex Development Divalent Cations Drug Interactions Elements Environment Eukaryota Future Genome Genotype Health Hepatitis C Hepatitis C virus Hepatitis C virus p7 protein In Vitro Influenza Investigation Ions Knowledge Life Cycle Stages Lipids Liposomes Liver diseases Mediating Membrane Methods Molecular Virology Mutation Nature Permeability Pharmaceutical Chemistry Process Production Prokaryotic Cells Proteins RNA Reading Reporting Research Role Solutions Structure Testing Therapeutic Titrations Vaccines Viral Virion Virus Virus Assembly anti-hepatitis C base drug development extracellular in vivo inhibitor/antagonist interdisciplinary approach mutant novel novel strategies patch clamp protein protein interaction research study small molecule solid state nuclear magnetic resonance virology

项目摘要

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.

描述（由申请人提供）：本提案旨在结合结构和功能方法研究丙型肝炎病毒（HCV）病毒孔蛋白 p7 的功能和治疗潜力。 HCV基因组编码的p7蛋白是病毒复制所必需的；它已被证明可以促进传染性病毒粒子的有效组装和释放。在膜中，p7 形成阳离子选择性通道。我们实验室最近解决的 p7 通道结构显示了病毒开发的一种新颖的结构，可以传导阳离子跨膜。该结构还揭示了与已知Ca2+/Mg2+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。与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这一事实表明离子渗透性在这些过程中发挥着作用，并促使新的研究更好地确定这一作用。 p7 通道也被作为抗 HCV 靶点，因为阻断通道活性会减少感染性病毒后代的产生。几种化合物已被证明可以抑制通道活性，包括也能阻断流感 M2 通道的金刚烷衍生物。这些药物相互作用可以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何处作用于 p7 通道尚不清楚。我们建议采用生物物理学、分子病毒学和药物化学等多学科方法来研究阳离子传导机制、通道活性对病毒组装和释放的影响以及已知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。