Discovery of long-acting, chemoprotective antimalarial compounds

摘要 为了发现下一代化学保护性抗疟疾药物的线索，我们测试了超过50万种化合物 他们的能力，以抑制肝脏阶段的发展，表达疟原虫（681与 IC50 < 1 µM）。聚类分析确定了有效的和以前未报道的支架家族，以及 以前与化学预防相关的其他系列。通过多种表型的进一步测试 预测阶段特异性和多物种抗疟活性的测定揭示了化合物类别， 可能会缓解血液阶段和其他只能预防疟疾的症状。目标 使用功能测定、体外进化或最有效血液的代谢谱进行鉴定 阶段活性支架揭示了多种线粒体抑制剂，但也有可能是新的化合物， 行动机制。整个数据集提供了数百种新的化学型和支架家族 （共享核心结构的化合物），其可用于进一步的药物开发以用于治疗， 预防疟疾。在这里，我们建议对1-2个支架系列进行命中以引导优化， 年，合成约750种化合物。选择化合物（10%）进行测试， 微粒体稳定性、蛋白质结合、hERG和视网膜电图抑制。药代动力学和预防性动物 每年将对约10种化合物进行模型试验。此外，我们将探讨是否有希望 先导物可转化为前药形式，其可作为肌内注射给药， 持久的化学预防打击导致优化将伴随着调查的机制 使用一套不同的方法，包括体外进化和整体进化， 基因组分析我们的目标是开发可能预防疟疾发展的治疗方法， 使用方便，优于现有药物上级。 .

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. .