Influenza A virus NS1 and PI3 Kinase: A structural investigation of their biological interaction

甲型流感病毒是严重的人类和动物疾病的罪魁祸首，引起季节性爆发，更罕见的是，世界范围内的大流行，猪流感？这是最新的例子。甲型流感病毒是相对简单的病毒，只制造少数病毒蛋白。其中一种蛋白质称为NS1，在实验室中对病毒复制（生长）不是必需的，但对病毒在人或动物中建立感染是必需的。它具有多种功能，包括抵消感染个体（宿主）对病毒的防御，并促进病毒复制。为了执行这些功能，NS1蛋白必须与许多宿主细胞蛋白相互作用。这项工作的目的是通过确定蛋白质的形状，确定NS1的哪些部分负责其与特定宿主细胞蛋白质的结合，并更好地确定这些不同的相互作用在病毒的生命周期中发挥什么作用，来进一步确定NS1蛋白如何执行这些功能。利用从这些研究中获得的信息可能为开发新型抗病毒药物（通过阻断NS1的功能起作用）和改进疫苗设计铺平道路。事实上，与MRC技术公司合作，这些提案的一部分涉及开发和使用筛选来鉴定与NS1相互作用的化合物，这些化合物具有抗病毒活性，随后可能被开发为抗流感病毒药物。

Influenza A viruses are responsible for serious human and animal diseases, causing seasonal outbreaks and, more rarely, worldwide pandemics, the ?swine flu? being the latest example. Influenza A viruses are relatively simple viruses, making only a few virus proteins. One of these proteins, termed NS1, is not essential for virus replication (growth) in the laboratory but is required for the virus to establish infections in people or animals. It has multiple functions, including counteracting the infected individuals (host) defences against viruses, and in promoting virus replication. To perform these functions the NS1 protein has to interact with many host cell proteins. The aim of this work is to further define how the NS1 protein performs these functions by determining the shape of the protein, defining which parts of NS1 are responsible for its binding to specific host cell proteins, and to better define what roles these different interactions play during the life cycle of the virus. Using the information gained from these studies may pave the way to development of novel anti-viral drugs (which would work by blocking the function(s) of NS1) and the improvement of vaccine design. Indeed, in collaboration with the MRC Technology, part of these proposals are concerned with developing and using screens to identify compounds that interact with NS1 and which have anti-viral activity that may be subsequently developed as anti-influenza virus drugs.