Small Molecule West Nile Virus Inhibitors

小分子西尼罗河病毒抑制剂

• 批准号: 7404500
• 负责人: KAREN G. ANTHONY
• 金额: $ 20.1万
• 依托单位: L2 DIAGNOSTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-03 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7404500
• 关键词: Animal Model; Antiviral Agents; Biological Assay; Categories; Cell Line; Characteristics; Collection; Culicidae; Dengue; Development; Disease; Doctor of Philosophy; Drug Kinetics; Elderly; Emerging Communicable Diseases; Evaluation; Flavivirus; Flavivirus Infections; Future; Goals; High Prevalence; Human; Human Cell Line; Image Analysis; Immune system; In Vitro; Lead; Libraries; Medical; Metabolism; National Institute of Allergy and Infectious Disease; Numbers; Outcome Study; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase II Clinical Trials; Property; Public Health; Recruitment Activity; Research; Screening procedure; Services; Therapeutic; Toxicology; Universities; Validation; Virus; Virus Diseases; Virus Inhibitors; West Nile virus; Work; absorption; assay development; base; biodefense; cytotoxicity; design; desire; drug development; drug discovery; genotoxicity; high throughput screening; improved; in vivo; inhibitor/antagonist; mouse model; pathogen; programs; small molecule; virology

DESCRIPTION (provided by applicant): Due to its high prevalence and its ability to cause severe disease in humans for which treatments are unavailable, West Nile (WN) virus has become an important public health concern in the U.S. The unmet medical need of developing effective WN virus therapeutics has been recognized by NIAID, which includes several flaviviruses in its current list of category A-C pathogens. The long-term objective of this project is to develop a small molecule therapeutic to treat severe West Nile (WN) virus infections in humans. The specific goal of this study is to identify small molecule inhibitors of WN virus by high throughput screening (HTS) and select among them lead compounds for future drug development. To this end, we have developed an in vitro WN virus infection assay using wild type virus and a human cell line. This assay was adapted to high-throughput format and was used to screen a small library of compounds from which three previously unknown WN virus inhibitors were identified. The Phase I project will expand this repertoire by screening additional compound libraries. `Screening hits' will then be critically evaluated for potency, selectivity, cytotoxicity and `druggability' in order to select lead candidates for detailed drug characterizations in Phase II studies. Successful development of a small molecule therapeutic for WN virus infections should provide the basis for similar therapeutics to treat other flavivirus infections of wider global importance, such as dengue fever. West Nile (WN) virus causes severe illness in the elderly and people with compromised immune systems. The virus is transmitted by mosquitoes and is widespread in the USA. There is no proven treatment available. This research will identify small molecule drugs to treat illness caused by WN virus infections in humans.

描述（由申请人提供）：由于其高流行及其在无法获得治疗的人类中引起严重疾病的能力，西尼罗河（WN）病毒已成为美国的重要公共卫生关注点，因此，NIAID认识到有效的WN病毒治疗剂的未满足医学需求已被NIAID认识到NIAID，其中包括当前A-C Pathery of Cathemens of Cathemens of Cathemens of Catherys of Cathemens of Cathemens。 该项目的长期目标是开发一种小分子治疗性，以治疗人类严重的西尼罗河（WN）病毒感染。这项研究的具体目标是通过高吞吐量筛选（HTS）鉴定WN病毒的小分子抑制剂，并选择其中的铅化合物以进行未来的药物开发。为此，我们使用野生型病毒和人类细胞系开发了体外WN病毒感染测定法。该测定法适用于高通量格式，并用于筛选一个小型化合物库，从中鉴定出三种以前未知的WN病毒抑制剂。 I阶段项目将通过筛选其他复合库来扩展此曲目。然后，将对“筛选命中”进行严格评估，以评估有效性，选择性，细胞毒性和“可药物性”，以便在II期研究中选择铅候选者进行详细的药物表征。 成功开发用于WN病毒感染的小分子治疗性应为类似的治疗药物治疗其他全球重要性（例如登革热）的类似疗法的基础。 西尼罗河（WN）病毒在老年人和免疫系统受损的人中导致严重疾病。该病毒是由蚊子传播的，在美国广泛。没有可靠的治疗方法。这项研究将确定小分子药物以治疗人类WN病毒感染引起的疾病。