Small molecule ligand interactions

丙型肝炎病毒(丙型肝炎病毒)是世界上的一个主要健康问题。这是一种主要影响肝脏的慢性疾病，目前还没有治愈方法。虽然干扰素-α和利巴韦林是目前使用的治疗方法，但这种方法有许多缺点。最近关于丙型肝炎病毒包膜E2与人CD81 Tetraspanin蛋白结合的报道为寻找新的药物提供了有价值的新靶点，这些药物可以阻断丙型肝炎病毒与人类细胞的这种最初结合。CD81(TapA，抗增殖抗体的靶标)是一个236个残基的蛋白，是Tetraspanin家族的成员。对CD81和E2的了解激发了干扰丙型肝炎病毒与人类细胞结合的新方法。我们的目标是：1-鉴定能够与含有CD81的星形胶质细胞结合的小分子。我们的假设是，我们将识别与CD81结合的新的合成和天然物质，并防止丙型肝炎病毒与人类细胞融合。我们的方法将是检查在美国和其他国家获得的合成和天然产物的文库，以了解它们与CD81结合的能力和96孔高通量检测系统。2-确定将与包膜蛋白(E1和E2)结合并抑制或干扰丙型肝炎病毒与人类细胞的结合和融合的化合物。我们将确定在细胞培养中抑制丙型肝炎病毒代理病毒(rVSV，包含包膜蛋白E1和E2)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出与CD81或包膜蛋白结合非常特异的新分子。事实证明，病毒在病毒生命周期中的附着和进入是攻击流感和艾滋病毒等其他病毒的有效切入点。从模型和先导化合物中获得的见解应该会导致高效的治疗和/或预防丙型肝炎病毒感染的新方法。

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.