Discovery of antiviral inhibitors for the treatment of orthopoxvirus infections

项目总结 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， 仅在二十世纪就造成3-5亿人死亡，直到1980年被最终根除。 在消灭天花病毒后，全球疫苗接种计划最终停止，因此，大多数 世界上一半的人口不再受到天花的免疫保护，也不再享受交叉- 对其他正痘病毒的保护。然而，有两种药物被批准用于治疗天花疾病，两者都是 化合物有很大的局限性。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。在第一阶段资助期内，我们将执行命中结果 反对拥有200,000种具有最佳类药物特性的化合物的活动。涌现的高质量热门产品 将接受后续测试，以调查其效力、选择性和 作用机制。其中最有趣的化合物将受到药物化学驱动 点击到领先，以探索结构-活性关系(SAR)。这个项目的总体目标是发现一个或 更新颖的铅系列，被定义为一种化学型抑制剂，显示出易处理的SAR，有效 对天花病毒和其他正痘病毒的抗病毒活性，细胞毒性最小。在这些方面取得成功 Endavors将触发第二阶段申请的提交，该申请将使计划从早期的领先地位推进 从优化到候选人选拔。

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.