Small molecule ligand interactions

小分子配体相互作用

• 批准号: 6502897
• 负责人: DUANE D MILLER
• 金额: $ 18.34万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6502897
• 关键词: CD antigens; antiviral agents; astrocytes; cooperative study; drug discovery /isolation; hepatitis C; hepatitis C virus; intermolecular interaction; ligands; tissue /cell culture; virus infection mechanism

Hepatitis C virus (HCV) represents a major health problem for the world. It is a chronic disease that effects mainly the liver and currently there is no cure. Although interferon-alpha and ribavirin are the currently used therapy this approach has many shortcomings. The recent report that the HCV envelope E2 binds to the human CD81 tetraspanin protein has provided valuable new targets for the search for new agents that could block this initial binding of the HCV to human cells. CD81 (TAPA, Target of the Anti-Proliferative Antibody) is a 236-residue protein and a member of the tetraspanin family. The knowledge about CD81 and E2 has stimulated new approach of interfering with the HCV binding to human cells. Our objectives are to: 1- Identify small molecules that will bind to astrocytes containing CD81. Our hypothesis states we will identify new synthetic and natural substances that bind to CD81 and prevent the fusion of HCV with the human cells. Our approach will be to examine libraries of synthetic and natural products obtained in the United States and other countries for their ability to bind to CD81 and a 96 well high throughput assay system. 2- Identify compounds that will bind to the envelop proteins (E1 and E2) and inhibit or interfere with the binding and fusion of the HCV virus to human cells. We will identify compounds that inhibit the spread of a HCV surrogate virus (rVSV, contain envelope proteins, E1 and E2) in cell culture. 3- Model the interaction of CD81 protein and the envelope proteins (E1 and E2) and to show how molecules can interfere with this interaction. Insights gained from this work will aid in the design of new molecules that will be very specific in binding to CD81 or the envelope proteins. The viral attachment and entry in the viral life-cycle has proven to be an effective point to attack with other viruses such as influenza and HIV. Insights gained from modeling and lead compounds should lead to a highly effective treatment and or new methods for the prevention of the HCV infection.

丙型肝炎病毒（HCV）代表了世界的主要健康问题。这是一种慢性疾病，主要影响肝脏，目前无法治愈。尽管干扰素 - 阿尔法和利巴韦林是当前使用的疗法，但这种方法有许多缺点。最近的报告HCV包膜E2与人CD81四叠胶质素蛋白结合，为搜索可能阻止HCV对人类细胞的初始结合的新药物提供了宝贵的新目标。 CD81（TAPA，抗增殖性抗体的靶标）是236个残留蛋白，也是四翼胺家族的成员。关于CD81和E2的知识刺激了干扰与人类细胞的HCV结合的新方法。我们的目标是：1-识别将与含有CD81的星形胶质细胞结合的小分子。我们的假设指出，我们将确定与CD81结合并防止HCV与人类细胞融合的新合成和天然物质。我们的方法是检查在美国和其他国家 /地区获得的合成和天然产品的库，以便它们与CD81结合和96个高吞吐量测定系统的能力。 2-识别将结合被包膜蛋白（E1和E2）的化合物，并抑制或干扰HCV病毒与人类细胞的结合和融合。我们将确定抑制HCV替代病毒传播（RVSV，包含包膜蛋白，E1和E2）的化合物。 3-模拟CD81蛋白和包膜蛋白（E1和E2）的相互作用，并显示分子如何干扰这种相互作用。从这项工作中获得的见解将有助于设计新分子，这些分子在与CD81或包膜蛋白结合的结合中非常具体。事实证明，病毒生命周期中的病毒依恋和进入是对其他病毒（例如流感和艾滋病毒）攻击的有效点。从建模和铅化合物中获得的见解应导致高效的治疗方法和 /或新方法预防HCV感染。