Novel anti-viral agents to treat influenza

描述（由申请人提供）：每年流感流行影响约5% - 15%的世界人口，估计每年死亡人数在250,000 - 500,000之间，其中包括美国约30,000人死亡和200,000人住院治疗。此外，由于20世纪记录了三次这样的大流行，由新出现的病毒株引起严重流感大流行的可能性非常高。其中最具破坏性的是1918年的西班牙流感，据估计全球有4000万人死亡。每年接种的季节性流感疫苗只能部分有效地预防这种疾病。同样，目前可用的抗流感药物，如金刚烷胺和奥司他韦，只能部分有效地治疗，而且还存在病毒耐药性的问题。因此，迫切需要额外的抗流感治疗，攻击病毒生物学未开发的方面。拟议中的研究旨在开发对抗流感病毒的新药。流感病毒的NS1蛋白是一种有吸引力的药物靶点，因为它是病毒在体内复制所必需的。因此，抑制NS1功能的药物有望阻止病毒复制，从而阻止疾病。已经确定了几种在感染过程中特异性抑制NS1功能的化合物。这些化合物代表了进一步药物开发的起点，也抑制了细胞培养中的病毒复制。本提案的目标是进行结构-活性和可行性研究，以确定如何对第一代化合物进行化学修饰，以提高其效力，同时限制其细胞毒性。在目标1中，药物化学方法将用于制造化学衍生物的初始集。这些化合物的设计将探测由原型活性化合物定义的主结构周围的化学空间。在特异性目标2中，衍生物将使用一组依赖于NS1蛋白功能的生物测定法进行测试。这些包括病毒复制、干扰素mRNA的诱导以及与多种细胞成分（包括dsRNA和特定细胞蛋白）的物理结合。这些研究的终点将是为未来的开发和动物试验确定有效的先导化合物。

DESCRIPTION (provided by applicant): Yearly influenza epidemics affect about 5 - 15% of the world's population and estimates of annual mortality range from 250,000 - 500,000, including approximately 30,000 deaths and 200,000 hospitalizations in the United States. In addition, the likelihood of a severe influenza pandemic caused by a newly emergent strain of the virus is very high, given that three such pandemics were recorded in the 20th century. The most devastating of these, the 1918 Spanish Flu, was responsible for an estimated 40 million deaths worldwide. The annual vaccine for seasonal influenza is only partially effective in prevention of the disease. Likewise, currently available anti-influenza drugs such as amantadine and oseltamavir are only partially effective in treatment and also suffer from problems of viral resistance. Therefore there is an urgent need for additional anti-influenza therapeutics that attack unexploited aspects of viral biology. The proposed research is directed at developing new drugs that can combat influenza virus. The NS1 protein of influenza virus is an attractive drug target because it is essential for virus replication in vivo. Therefore drugs that inhibit NS1 function are expected to block virus replication, and hence disease. Several compounds that specifically inhibit NS1 function during infection have been identified. These compounds, which represent starting points for further drug development, also inhibit virus replication in cell culture. The goals of this proposal are to perform structure-activity and feasibility studies to determine how the first-generation compounds can be chemically modified to increase their potency while at the same time limiting their cellular toxicity. In Aim 1, medicinal chemistry approaches will be used to make initial sets of chemical derivatives. The design of these compounds will probe the chemical space around the backbone structures defined by the prototype active compounds. In Specific Aim 2, the derivatives will be tested using a set of biological assays that depend on the function of the NS1 protein. These include virus replication, induction of interferon mRNA, and physical binding to several cellular components including dsRNA and specific cellular proteins. The endpoint of these studies will be the identification of potent lead compounds for future development and animal testing. PUBLIC HEALTH RELEVANCE: Yearly influenza epidemics affect about 5 - 15% of the world's population and estimates of annual mortality range from 250,000 - 500,000, including approximately 30,000 deaths and 200,000 hospitalizations in the United States. The proposed research is directed at developing new drugs that can combat the influenza virus, the virus that causes influenza.