Development of Antiviral Strategies for Enveloped Virus

这项建议将利用我们实验室正在进行的研究，这些研究正在检查 三组病毒的蛋白质结构-功能关系：黄病毒，黄病毒 甲型病毒和丝状病毒。使用从这些研究中获得的信息以及 根据先前获得的初步数据，我们将确定并针对病毒的特定方面 抑制化合物发展的复制循环。黄病毒由一个属组成 在正链RNA病毒的黄病毒科内。它的许多成员导致了重大的 人类的疾病。黄病毒的几个例子包括登革热、黄热病、西尼罗河病毒和 壁虱传播脑炎。我们还将对甲型病毒进行研究，甲型病毒是一种正链病毒 在Togaviridae科中发现的RNA病毒。甲型病毒的几个例子是辛德比斯和 委内瑞拉马脑炎。此外，我们还将检测埃博拉病毒的主要糖蛋白GP1 病毒使用结构和计算方法，并利用这些信息开发 抗病毒药物。所有三组病毒都含有被建议尽可能多的成员 生物恐怖主义特工。针对这些病毒的有效疫苗很少，也没有有效的抗病毒药物。 探员们。结合分子遗传学，我们的结构研究表明有可能 病毒复制周期中可能易受抗病毒药物抑制的步骤。这支队伍 这里描述的研究人员汇集了各种实验策略，这些策略将被带到 致力于抗病毒药物的开发。理查德·库恩将协调这些努力，并将 负责建立筛选潜在化合物的分析方法。大卫·桑德斯将携带 使用假型粒子进行进入和融合分析。迈克尔·罗斯曼和珍妮特·史密斯将 进行X射线结晶学研究，以检查病毒蛋白和结合抑制物的复合体。 抑制剂的设计和合成将由Carol Post使用核磁共振和分子 动态模拟，以及马克·库什曼，他将直接合成这种化合物。

This proposal will take advantage of on-going studies in our laboratories that are examining the structure-function relationships of proteins from three groups of viruses: the flaviviruses, the alphaviruses, and the filoviruses. Using information derived from these studies as well as preliminary data previously obtained, we will identify and target specific aspects of the virus replication cycle for the development of inhibitory compounds. The flaviviruses comprise a genus within the family Flaviviridae of plus-strand RNA viruses. Many of its members cause significant disease in humans. Several examples of flaviviruses include dengue, yellow fever, West Nile, and tick-borne encephalitis. We will also carry out studies with the alphaviruses, a genus of plus-strand RNA viruses found in the Togaviridae family. Several examples of alphaviruses are Sindbis and Venezuelan equine encephalitis. In addition, we will examine the major glycoprotein GP1 of Ebola virus using structural and computational approaches and utilize this information to develop antivirals. All three groups of viruses contain members that have been suggested as possible bioterrorism agents. There are few effective vaccines for these viruses and no efficacious antiviral agents. In combination with molecular genetics, our structural studies have suggested possible steps in the virus replication cycle that may be susceptible to inhibition by antivirals. The team of investigators described here brings together diverse experimental strategies that will be brought to bear on the development of antivirals. Richard Kuhn will coordinate the efforts and will be responsible for establishing assays for screening of potential compounds. David Sanders will carry out entry and fusion assays using pseudotyped particles. Michael Rossmann and Janet Smith will carry out X-ray crystallographic studies to examine complexes of viral proteins and bound inhibitors. The design and synthesis of inhibitors will be done by Carol Post, using NMR and molecular dynamic simulations, and Mark Cushman, who will directly synthesize such compounds.