Discovery of Broad Spectrum Dengue Virus Proteinase Inhibitors

广谱登革热病毒蛋白酶抑制剂的发现

• 批准号: 7536362
• 负责人: ALAN THOMAS JOHNSON
• 金额: $ 30万
• 依托单位: PANTHERA BIOPHARMA, LLC
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-11 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7536362
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; 3-Dimensional; Active Sites; Antiviral Agents; Bacteria; Binding Sites; Biochemical; Biological Assay; Botulinum Toxins; Case Study; Categories; Cells; Cessation of life; Cocrystallography; Collection; Culicidae; Data; Dengue; Dengue Hemorrhagic Fever; Dengue Shock Syndrome; Dengue Virus; Development; Digit structure; Disease; Docking; Drug Design; Electronics; Endopeptidases; Environment; Enzyme Kinetics; Enzymes; Family; Flavivirus; Fluorescence Resonance Energy Transfer; Geographic Distribution; Geographic Locations; Goals; Housing; Human; In Vitro; Incidence; Infection; Infectious Agent; Lead; Libraries; Life; Life Cycle Stages; Light; Location; Measures; Methods; NS3 proteinase; National Institute of Allergy and Infectious Disease; Panthera; Peptide Hydrolases; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Physiological; Population; Preclinical Drug Evaluation; Process; Property; Protease Inhibitor; Proteins; Public Health; Range; Research; Risk; Score; Screening procedure; Series; Serine Protease; Serotyping; Site; Structural Protein; Structure; Testing; Therapeutic; Vaccines; Vendor; Viral; Virus; Virus Diseases; West Nile virus; analog; anthrax lethal factor; arbovirus disease; assay development; base; biochemical model; burden of illness; cytotoxicity; dengue virus NS3; drug discovery; experience; high throughput screening; inhibitor/antagonist; member; molecular modeling; numb protein; pathogen; prevent; prophylactic; protein expression; small molecule; small molecule libraries; virtual

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.

描述（由申请人提供）：超过一半的世界人口有登革热病毒感染的风险，登革热病毒是Flavivirus家族的寄生成员，由四种不同的血清型组成。大约50至1亿个感染每年发生，估计有500,000例威胁生命的登革热出血热或登革热综合症。由于登革热感染的发病率增加和扩散地理分布，因此被认为是一种新兴疾病，被NIAID鉴定为优先病原体的类别。尽管与登革热感染相关的疾病负担很大，但目前尚无批准的疫苗或抗病毒药。该项目的目的是通过阻断登革热病毒NS3蛋白的蛋白水解活性来发现和开发抑制登革热病毒感染的抗病毒药物。蛋白酶是病毒成熟的关键酶，已经证明了黄病毒蛋白酶的抑制作用可大大减少病毒复制。基于结构的药物设计将为有效和病毒特异性蛋白酶抑制剂提供快速途径。我们将使用化学库实际上筛选活动站点。这些靶标将通过分子建模通过虚拟药物筛查的过程进行检查，以找到潜在的抑制剂化合物，然后在项目过程中利用生化测定法进行实验测试。基于细胞的测定法也将用于在生理环境中确认病毒抑制。与其他3种血清型相比，活性与血清型2的登革热NS3蛋白酶的化合物也将进行测试，以鉴定潜在的广泛谱登革热抗病毒疗法。在第一阶段结束时，我们打算至少选择一个具有高效力的铅序列，以优化用于生产有效的广泛的登革热抗病毒药药，以及在II期期间可能的其他黄病毒。公共卫生相关性：登革热比任何其他丁香病毒疾病都会引起更多的疾病和死亡，并正在扩散到新的地理区域，并在2006年报告了925,000例病例。没有商业的预防性或治疗性可用于治疗这种疾病。我们的策略是发现和优化口服可用的抗病毒药物，以预防和治疗登革热感染，并具有潜在的广谱活性与所有黄素病毒。