Small molecule ligand interactions

小分子配体相互作用

• 批准号: 6662100
• 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: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6662100
• 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）是世界的一个主要健康问题。这是一种主要影响肝脏的慢性疾病，目前尚无治愈方法。尽管干扰素-α和利巴韦林是目前使用的疗法，但该方法有许多缺点。最近关于 HCV 包膜 E2 与人类 CD81 四跨膜蛋白结合的报道为寻找能够阻止 HCV 与人类细胞的这种初始结合的新药物提供了有价值的新靶点。 CD81（TAPA，抗增殖抗体的靶标）是一种 236 个残基的蛋白质，是四跨膜蛋白家族的成员。关于 CD81 和 E2 的知识激发了干扰 HCV 与人体细胞结合的新方法。我们的目标是： 1- 鉴定可与含有 CD81 的星形胶质细胞结合的小分子。我们的假设表明，我们将鉴定出与 CD81 结合并阻止 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获得的合成和天然产物文库与 CD81 结合的能力和 96 孔高通量测定系统。 2- 鉴定与包膜蛋白（E1 和 E2）结合并抑制或干扰 HCV 病毒与人类细胞结合和融合的化合物。我们将鉴定抑制 HCV 替代病毒（rVSV，含有包膜蛋白、E1 和 E2）在细胞培养物中传播的化合物。 3- 模拟 CD81 蛋白和包膜蛋白（E1 和 E2）的相互作用，并展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，这些分子将非常特异性地结合 CD81 或包膜蛋白。病毒生命周期中的病毒附着和进入已被证明是攻击流感和艾滋病毒等其他病毒的有效点。从建模和先导化合物中获得的见解应该会产生高效的治疗方法和/或预防 HCV 感染的新方法。