Molecular Target(s) for Interruption of HBV Infection

阻断 HBV 感染的分子靶点

• 批准号: 7054040
• 负责人: Jisu Li
• 金额: $ 22.04万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-15 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7054040
• 关键词: animal viral hepatitis; antiviral agents; antiviral antibody; carboxypeptidase; decarboxylases; disease /disorder model; duck hepatitis B virus; ducks; enzyme activity; enzyme mechanism; glycine; hepatitis B; host organism interaction; liver cells; liver neoplasms; prohormone convertase; protein localization; protein protein interaction; small interfering RNA; tissue /cell culture; virus envelope; virus infection mechanism; virus protein; virus receptors; virus related neoplasm /cancer

DESCRIPTION (provided by applicant): Hepatitis B virus (HBV) is an oncogenic virus. An estimated 400 million individuals worldwide are infected with HBV leading to chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The early events of HBV infection are poorly defined due to the low signal intensity, transient and dynamic nature of the entry process, and lack of a systemic approach to identify the cellular components required for individual steps. Once characterized, these host factors may serve as critical targets for therapeutic intervention, thus reducing the rate of chronic hepatitis and ensuing liver cancer. Duck hepatitis B virus (DHBV), the related hepatotropic DNA virus may serve as a model system for the identification of viral receptor/co-factors as well as for the evaluation of novel molecular targets for intervention of hepadnavirus infection. We have previously identified and cloned two DHBV pre-S envelope-interacting proteins: p170 (carboxypeptidase D, DCPD) and p120 (glycine decarboxylase). The DCPD has been established as a DHBV docking receptor but fails to confer DHBV susceptibility of cell lines, suggesting that other cellular co-factors are necessary for establishing productive viral infection. The p120 is distributed only in DHBV infectible tissues and essential for a post-binding step of the DHBV life cycle. Optimal p120 binding in vitro requires truncation of the pre-S domain, which contains a putative cleavage site for PC7, a proprotein convertase. Our long-term goal is to understand virus-host interactions in the viral entry pathway and identify cellular targets for therapeutic intervention. The present application will initiate investigations on the mode of p120 action. Our specific aims are: (1). Investigate the molecular basis whereby p120 mediates productive DHBV infection; (2). Determine the contribution of proprotein convertases to DHBV infectivity; and (3). Evaluate p120 as well as DCPD as molecular targets for intervention of DHBV infection. We hope these studies will contribute to the understanding of the early events of hepadnavirus infection and may lead to the development of novel antiviral strategies for prevention of HBV induced liver cancer.

描述（由申请方提供）：B肝炎病毒（HBV）是一种致癌病毒。 据估计，全世界有4亿人感染HBV，导致慢性肝炎、肝硬化和肝细胞癌（HCC）。 HBV感染的早期事件由于低信号强度、进入过程的瞬时和动态性质以及缺乏系统方法来鉴定各个步骤所需的细胞组分而定义不清。 一旦特征化，这些宿主因素可以作为治疗干预的关键目标，从而降低慢性肝炎和随后的肝癌的发生率。 鸭B肝炎病毒（DHBV），相关的嗜肝DNA病毒，可以作为一个模型系统的病毒受体/辅因子的鉴定，以及评价新的分子靶点干预嗜肝DNA病毒感染。 我们以前已经确定并克隆了两个DHBV前S酶相互作用蛋白：p170（羧肽酶D，DCPD）和p120（甘氨酸脱羧酶）。 DCPD已被确定为DHBV对接受体，但未能赋予细胞系DHBV易感性，表明其他细胞辅因子是建立生产性病毒感染所必需的。 p120仅分布于DHBV可感染的组织中，并且对于DHBV生命周期的后结合步骤是必需的。 最佳的p120体外结合需要截短的前S结构域，其中包含一个推定的切割位点的PC 7，前蛋白转化酶。 我们的长期目标是了解病毒进入途径中的病毒-宿主相互作用，并确定治疗干预的细胞靶点。 本申请将启动对p120作用方式的调查。我们的具体目标是：（1）。探讨p120介导DHBV感染的分子基础;确定前蛋白转化酶对DHBV感染性的贡献;（3）。评价p120和DCPD作为DHBV感染干预的分子靶点。我们希望这些研究将有助于了解嗜肝DNA病毒感染的早期事件，并可能导致开发新的抗病毒策略来预防HBV诱导的肝癌。