Molecular Target(s) for Interruption of HBV Infection

阻断 HBV 感染的分子靶点

• 批准号: 6925758
• 负责人: Jisu Li
• 金额: $ 22.47万
• 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 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6925758
• 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（由申请人提供）：乙型肝炎病毒（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)。 由于信号强度低、进入过程短暂和动态，并且缺乏系统方法来识别各个步骤所需的细胞成分，因此对 HBV 感染的早期事件的定义很差。 一旦确定特征，这些宿主因素可能成为治疗干预的关键目标，从而降低慢性肝炎和随之而来的肝癌的发病率。 鸭乙型肝炎病毒（DHBV）是相关的亲肝DNA病毒，可作为识别病毒受体/辅助因子以及评估干预嗜肝DNA病毒感染的新分子靶点的模型系统。 我们之前已经鉴定并克隆了两种 DHBV pre-S 包膜相互作用蛋白：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 敏感性，这表明其他细胞辅助因子对于建立有效的病毒感染是必需的。 p120 仅分布在 DHBV 感染组织中，对于 DHBV 生命周期的结合后步骤至关重要。 体外最佳的 p120 结合需要截断前 S 结构域，该结构域包含 PC7（一种前蛋白转化酶）的假定切割位点。 我们的长期目标是了解病毒进入途径中病毒与宿主的相互作用，并确定治疗干预的细胞靶点。 本申请将启动对p120作用模式的研究。我们的具体目标是：（1）。研究 p120 介导生产性 DHBV 感染的分子基础； （2）。确定前蛋白转化酶对 DHBV 感染性的贡献；和（3）。评估 p120 和 DCPD 作为干预 DHBV 感染的分子靶点。我们希望这些研究将有助于了解肝炎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乙型肝炎引起的肝癌。