Discovery of Broad Spectrum Dengue Virus Proteinase Inhibitors

描述（由申请人提供）：超过一半的世界人口有感染登革热病毒的风险，登革热病毒是由四种不同血清型组成的黄病毒家族的蚊媒成员。每年发生大约5000万至1亿例感染，导致估计500，000例危及生命的登革出血热或登革休克综合征。由于登革热感染的发病率增加和地理分布的扩大，它被认为是一种新出现的疾病，并被NIAID确定为A类优先病原体。尽管与登革热感染相关的重大疾病负担，但目前还没有批准的疫苗或抗病毒药物。该项目的目标是发现和开发通过阻断登革病毒NS3蛋白的蛋白水解活性来抑制登革病毒感染的抗病毒药物。蛋白酶是病毒成熟的关键酶，并且黄病毒蛋白酶的抑制已显示出显著减少病毒复制。基于结构的药物设计将提供一个快速的途径，有效的和病毒特异性蛋白酶抑制剂。我们将用化学文库来虚拟筛选活性位点。这些目标将通过虚拟药物筛选过程中的分子建模进行检查，以找到潜在的抑制剂化合物，然后利用在项目过程中优化的生化分析在体外进行实验测试。还将使用基于细胞的试验来确认在稍微更生理环境中的病毒抑制。对血清型2的登革NS3蛋白酶有活性的化合物也将对其他3种血清型进行测试，以鉴定潜在的广谱登革抗病毒治疗剂。在第一阶段结束时，我们打算选择至少一个具有高效力的先导系列进行优化，以在第二阶段期间生产有效的广谱登革热抗病毒药物和可能的其他黄病毒。公共卫生相关性：登革热比任何其他虫媒病毒疾病造成更多的疾病和死亡，并正在向新的地理区域蔓延，2006年报告了925 000例病例。没有商业预防剂或治疗剂可用于治疗该疾病。我们的策略是发现和优化口服抗病毒药物，以预防和治疗登革病毒感染，对所有黄病毒具有潜在的广谱活性。

DESCRIPTION (provided by applicant): Over half of the world population is at risk for infection by dengue virus, a mosquito borne member of the Flavivirus family that consists of four distinct serotypes. Approximately 50 to 100 million infections occur annually resulting in an estimated 500,000 cases of life threatening dengue hemorrhagic fever or dengue shock syndrome. Due to the increased incidence and spreading geographic distribution of dengue infection, it is considered to be an emerging disease and is identified by NIAID as a category A priority pathogen. Despite the significant disease burden associated with dengue infection there is presently no approved vaccine or antiviral drug. The goal of this project is to discover and develop antiviral drugs that inhibit dengue virus infection by blocking the proteolytic activity of the dengue virus NS3 protein. The protease is a key enzyme in viral maturation and inhibition of flavivirus protease has been shown to dramatically reduce viral replication. Structure based drug design will provide a rapid path to potent and virus specific protease inhibitors. We will virtually screen the active site with a chemical library. These targets will be examined by molecular modeling through a process of virtual drug screening to find potential inhibitor compounds that will then be tested experimentally in vitro utilizing biochemical assays optimized during the course of the project. A cell based assay will also be used to confirm virus inhibition in a slightly more physiological environment. Compounds that are active versus the Dengue NS3 proteinase of serotype 2 will also be tested versus the other 3 serotypes, in order to identify potential broad spectrum dengue antiviral therapeutics. At the conclusion of Phase I we intend to select at least one lead series with high potency to be optimized toward producing an effective broad spectrum dengue antiviral drug and possible other Flaviviruses during Phase II. PUBLIC HEALTH RELEVANCE: Dengue fever causes more illness and death than any other arboviral disease and is spreading into new geographic areas, with 925,000 cases reported in 2006. No commercial prophylactic or therapeutic is available to treat the disease. Our strategy is to discover and optimize orally available antiviral drugs to prevent and treat Dengue virus infections, with potential broad spectrum activity versus all flaviviruses.