Discovery of long-acting, chemoprotective antimalarial compounds

摘要 为了寻找下一代化学保护性抗疟疾药物的先导药物，我们测试了&gt；50万种化合物 它们有能力抑制表达荧光素酶的疟原虫在肝脏阶段的发育(681 一个IC50；1微米)。聚类分析确定了有效的和以前未报道的支架家族以及 以前与化学预防有关的其他系列。通过多表型进一步测试 预测特定阶段和多物种抗疟疾活性的分析显示，化合物类 可能会缓解血液期的症状，而其他只能预防疟疾的药物。目标 使用功能分析、体外进化或代谢图谱鉴定最有效的血液 阶段活性支架显示多种线粒体抑制物，但也有可能具有新的化合物 行动机制。总数据集提供了数百个新的化学类型和支架家族 (具有核心结构的化合物)，可用于进一步的治疗药物开发和 预防疟疾。在这里，我们建议对每个脚手架族执行Hit to Lead优化 一年，合成了大约750种化合物。将对选定的化合物(10%)进行测试 微粒体稳定性、蛋白质结合、HERG和CYP抑制。药代动力学与预防动物 每年将对大约10种化合物进行模型试验。此外，我们还将探讨是否有希望 铅可以转化为前药形式，可以肌肉注射的形式提供长期的- 持久的化学预防。命中到领先优化将伴随着对机制的调查 使用一套不同的方法对六个支架家族的作用进行比较，包括体外进化和整体 基因组分析。我们的目标是开发可以防止疟疾发展的治疗方法，即 使用方便，优于现有药物。 。

ABSTRACT To discover leads for next-generation chemoprotective antimalarial drugs, we tested >500,000 compounds for their ability to inhibit liver-stage development of luciferase-expressing Plasmodium parasites (681 with an IC50 < 1 µM). Cluster analysis identified potent and previously unreported scaffold families as well as other series previously associated with chemoprophylaxis. Further testing through multiple phenotypic assays that predict stage-specific and multispecies antimalarial activity revealed compound classes that are likely to provide symptomatic relief from blood-stage and others that only prevent malaria. Target identification using functional assays, in vitro evolution or metabolic profiling of the most potent blood stage-active scaffolds revealed multiple mitochondrial inhibitors but also compounds with likely new mechanisms of action. The total dataset provided hundreds of new chemotypes and scaffold families (compounds sharing a core structure) that may be used in further drug development for the treatment and prevention of malaria. Here we propose to perform hit to lead optimization on 1-2 scaffold families per year, synthesizing approximately ~750 compounds. Select compounds (10%) will be tested for microsomal stability, protein binding, hERG, and CYP inhibition. Pharmacokinetic and prophylactic animal model testing will be performed on ~10 compounds per year. In addition, we will explore whether promising leads can be converted to a prodrug form that can be given as intramuscular injection which provides long- lasting chemoprevention. Hit to lead optimization will be accompanied by investigation into the mechanism of action of six scaffold families using a suite of different methods including in vitro evolution and whole genome analysis. We aim to develop treatments that may prevent malaria from developing, that are convenient to use and which are superior to current medicines. .