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）：由于西尼罗河 (WN) 病毒的高患病率以及在人类中引起无法治疗的严重疾病的能力，西尼罗河 (WN) 病毒已成为美国重要的公共卫生问题。开发有效的治疗方法尚未得到满足的医疗需求WN 病毒疗法已获得 NIAID 的认可，NIAID 目前的 A-C 类病原体清单中包括几种黄病毒。 该项目的长期目标是开发一种小分子疗法来治疗人类严重的西尼罗河（WN）病毒感染。本研究的具体目标是通过高通量筛选（HTS）鉴定 WN 病毒的小分子抑制剂，并从中选择用于未来药物开发的先导化合物。为此，我们开发了一种使用野生型病毒和人类细胞系的体外 WN 病毒感染测定法。该测定适用于高通量形式，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。第一阶段项目将通过筛选额外的化合物库来扩展该库。然后，将对“筛选命中”的效力、选择性、细胞毒性和“成药性”进行严格评估，以便在第二阶段研究中选择主要候选药物进行详细的药物表征。 成功开发治疗 WN 病毒感染的小分子疗法，应该为治疗其他具有更广泛全球重要性的黄病毒感染（例如登革热）的类似疗法奠定基础。 西尼罗河 (WN) 病毒会导致老年人和免疫系统受损的人患上严重疾病。该病毒通过蚊子传播，在美国广泛传播。目前还没有经过证实的治疗方法。这项研究将确定小分子药物来治疗人类 WN 病毒感染引起的疾病。