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）：该提案旨在研究结构和功能方法的组合，研究乙型肝炎病毒（HCV）的Viroporin蛋白P7的功能和治疗潜力。由HCV基因组编码的P7蛋白是病毒复制所必需的。已显示它可以促进有效的组装和释放感染性病毒体的释放。在膜中，P7形成阳离子选择通道。最近在我们的实验室中解决的P7通道的结构表明，病毒开发了一种在整个膜上进行阳离子开发的新结构。该结构还揭示了部分类似于已知Ca2+/Mg2+通道的元素，这些元素为进一步的研究提供了了解通道机制的线索。像大多数毒蛋白一样，病毒组装过程中P7介导的阳离子传导的功能仍然难以捉摸。 P7形成明确定义的通道结构的事实表明，离子渗透性在这些过程中的作用，并敦促新的研究以更好地定义这一作用。 P7通道也被追求为抗HCV靶标，因为阻断了通道活性降低了传染性病毒后代的产生。已经证明了几种化合物可以抑制通道活性，包括也阻断流感M2通道的阿甘坦衍生物。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，但是这些化合物在P7通道上的作用以及何处是未知的。我们建议在生物物理学，分子病毒学和药物化学中采用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影响以及已知抑制剂的通道抑制结构碱基。从拟议的研究中获得的知识可能会带来开发用于治疗HCV感染的化合物的新机会。