Discovery of antiviral inhibitors for the treatment of orthopoxvirus infections

发现治疗正痘病毒感染的抗病毒抑制剂

• 批准号: 10761185
• 负责人: Glen Andrew Coburn
• 金额: $ 30万
• 依托单位: VENATORX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-24 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10761185
• 关键词: Adult; Africa; Animals; Antiviral Agents; Asia; Biological Assay; Biological Availability; Bioterrorism; Case Fatality Rates; Cells; Cessation of life; Cidofovir; Cowpox virus; Development; Disease; Disease Outbreaks; Domestic Animals; Dose; Drug Kinetics; Environment; Event; Exhibits; Exposure to; Family member; Funding; Future; Genetic; Geographic Distribution; Goals; Human; Immunization Programs; Immunologics; Incubated; Individual; Infant; Infection; Lead; Libraries; Middle East; Military Personnel; Molecular Target; Monkeypox virus; Oral; Orthopoxvirus; Pattern; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Population; Predisposition; Preparation; Prevention; Probability; Property; Public Health; Recording of previous events; Reporting; Resistance; Risk; Series; Small Business Innovation Research Grant; Smallpox; South America; Structure-Activity Relationship; Surface; Testing; Therapeutic; Toxic effect; USSR; Vaccination; Vaccines; Vaccinia; Vaccinia virus; Variant; Variola major virus; Viral; Viral Physiology; Virus; Virus Diseases; Virus Inhibitors; Wild Animals; Zoonoses; aerosolized; bioweapon; candidate selection; cross immunity; cytotoxicity; drug-like compound; high throughput screening; human disease; improved; indexing; inhibitor; lead optimization; lead series; monolayer; novel; novel virus; pandemic potential; pathogen; programs; response; small molecule; small molecule libraries; success; symposium; transmission process

PROJECT SUMMARY Smallpox (caused by variola virus infection) was one of the most destructive diseases in human history, resulting in 300-500 million deaths in the twentieth century alone until it was finally eradicated in 1980. Following elimination of variola virus, global vaccination programs were eventually halted and as a result, most of the world’s population is no longer immunologically protected from smallpox nor does it enjoy cross- protection to other orthopoxviruses. There are two drugs approved for smallpox disease, however, both compounds possess significant limitations. A lack of therapeutic options for treating orthopoxvirus infections continues to expose the population to grave risk from a smallpox bioweapon as well as future zoonotic orthopoxvirus infections. During the course of the Phase I funding period, we will execute a hit finding campaign against a library of >200,000 compounds with optimal drug-like properties. Quality hits that emerge from the assay will be subjected to follow-on testing that will investigate the potency, selectivity, and mechanism of action. The most interesting of these compounds will be subjected to medicinal chemistry driven hit-to-lead to explore structure-activity relationships (SAR). The overall goal of this project is to discover one or more novel lead series which is defined as a chemotype inhibitor that demonstrates tractable SAR, potent antiviral activity against variola virus and other orthopoxviruses with minimal cytotoxicity. Success in these endeavors will trigger the submission of a Phase II application that will advance the program from Early Lead Optimization through to Candidate Selection.

项目摘要 天花（由天花病毒感染引起）是人类历史上最具破坏性的疾病之一， 仅在20世纪就造成3 - 5亿人死亡，直到1980年才最终根除。 在天花病毒被消灭后，全球疫苗接种计划最终停止，因此，大多数人 世界人口的10%不再受到天花的免疫保护，也不享受交叉感染， 对其他正痘病毒的保护。有两种药物被批准用于天花疾病，然而， 化合物具有显著的局限性。缺乏治疗正痘病毒感染的治疗选择 继续使人口面临天花生物武器以及未来人畜共患病的严重风险 正痘病毒感染在第一阶段的资助期间，我们将执行命中发现 针对具有最佳药物样特性的> 200，000种化合物的库开展活动。高质量的热门歌曲 将进行后续检测，以研究效价、选择性和 作用机制。这些化合物中最有趣的将受到药物化学的驱动 Hit-to-Lead探索构效关系（SAR）。该项目的总体目标是发现一个或 更新颖的铅系列，其被定义为表现出易处理的SAR、有效的 抗天花病毒和其它正痘病毒的抗病毒活性，具有最小的细胞毒性。成功在这些 努力将触发提交第二阶段的申请，这将推动该计划从早期领先 优化到候选人选择。