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面临感染登革热病毒的风险，登革热病毒是黄病毒家族的一种蚊子传播的成员，由四种不同的血清型组成。每年大约发生5000万至1亿例感染，造成约50万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疾病负担很大，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抗病毒药物，通过阻断登革热病毒NS3蛋白的蛋白水解活性来抑制登革热病毒感染。黄病毒蛋白酶是病毒成熟的关键酶，抑制黄病毒蛋白酶可显著减少病毒复制。基于结构的药物设计将提供有效的和病毒特异性蛋白酶抑制剂的快速途径。我们将用化学文库对活性位点进行虚拟筛选。这些靶点将通过虚拟药物筛选过程中的分子建模来检测，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。一种基于细胞的试验也将用于确认在稍微生理一些的环境中病毒的抑制作用。对血清2型登革热NS3蛋白酶有活性的化合物也将与其他3种血清型进行测试，以确定潜在的广谱登革热抗病毒治疗方法。在I期结束时，我们打算选择至少一个高效的先导系列进行优化，以在II期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：登革热造成的疾病和死亡比任何其他虫媒病毒性疾病都多，并正在向新的地理区域蔓延，2006年报告了92.5万例病例。目前还没有商业上的预防或治疗药物可以治疗这种疾病。我们的战略是发现和优化口服抗病毒药物，以预防和治疗登革热病毒感染，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.