Optimization of antimalarials targeting multiple life stages of the parasite

项目概要/摘要 疟疾寄生虫是最致命的真核病原体之一，世界人口超过40% 有感染疟疾的危险由于对目前可用药物的耐药性越来越强， 对预防和治疗疟疾感染的新药的医疗需求。本补助金申请的重点是 优化两种新型抗疟药（2a和（R）-3a），以靶向出现的寄生虫的多个生命阶段 从我们以前对靶向顶质体的疟疾盒化合物MMV 008138的工作中。这些 使用基于原子性质场的虚拟配体筛选（VLS）的组合鉴定化合物， 一个包含500万种公开化合物和合成化学活动的图书馆。虽然2a和（R）-3a 与MMV 008138具有结构相似性并杀死无性血液阶段，其作用机制是 独立于顶质体。此外，MMV 008138仅影响无性血液阶段，而2a也会导致死亡 阶段V配子体，和（R）-3a弱杀死伯氏疟原虫肝阶段。对于每两个小说 化合物系列，我们将探讨：i）结构活性关系，控制效力，细胞选择性， ii）控制吸附、分布、代谢和排泄的结构性质关系;以及 iii）其潜在的作用机制和抗性。该项目的首要目标是优先考虑 具有新的作用机制、对疟原虫相对于人类宿主的高选择性的临床前先导物，和 与口服可利用的候选药物的开发相容的理化性质。两 该R01提案的主要目标是：1）结构上修饰2a（lead）和（R）-3a（hit）以优化体外 除杀配子和/或肝阶段活性外，还具有无性血液阶段效力、药物样性质，以及 药代动力学，单次经口给药ED 90 ≤ 10 mg/kg，达到体内伯氏疟原虫感染小鼠的疗效 对于2a类似物（晚期先导化合物）和（R）-3a系列（早期先导化合物），1 - 3次口服给药的ED 90 ≤ 40 mg/kg/天， 和2）鉴定2a和（R）-3a（或它们的更有效的）的抗疟作用机制和抗性 类似物）分别通过化学蛋白质组学和抗性选择方法。这件事的辅助目标是 建议是开发恶性疟原虫杀配子效力的结构-活性关系（SAR）， p.这两个系列的berghei肝阶段效力，并确定多阶段的共识药效团 活性（无性血液阶段效力加上杀配子和/或肝脏阶段效力）。有效 因此，以这种方式鉴定的化合物将很好地用于进一步的临床前开发。

PROJECT SUMMARY/ABSTRACT The malaria parasite is one of the most deadly eukaryotic pathogens and more than 40% of the world's population is at risk of contracting malaria. Due to growing resistance to currently available medications, there is a pressing medical need for new drugs to prevent and treat malaria infection. This grant application focuses on the optimization of two novel antimalarials (2a and (R)-3a) to target multiple life stages of the parasite that emerged from our previous work on the Malaria Box compound MMV008138 that targets the apicoplast. These compounds were identified using a combination of atomic property field-based virtual ligand screening (VLS) of a library of 5 million publicly available compounds and synthetic chemistry campaigns. Although 2a and (R)-3a bear a structural resemblance to MMV008138 and kill asexual blood-stages, their mechanism of action is independent of the apicoplast. In addition, whereas MMV008138 only affects asexual blood-stages, 2a also kills Stage V gametocytes, and (R)-3a weakly kills Plasmodium berghei liver-stages. For each of the two novel compound series, we will explore: i) structure activity relationships that control potency, cellular selectivity, and efficacy; ii) structure property relationships that govern adsorption, distribution, metabolism, and excretion; and iii) their potential mechanisms of action and resistance. The overarching goal of this project is to prioritize preclinical leads having novel mechanism of action, high selectivity for Plasmodium versus the human host, and physiochemical properties that are compatible with development of an orally available drug candidate. The two principal goals of this R01 proposal are to: 1) structurally modify 2a (lead) and (R)-3a (hit) to optimize in vitro asexual blood-stage potencies in addition to gametocicydal and/or liver stage activities, drug-like properties, and pharmacokinetics, achieving in vivo P. berghei-infected mice efficacy with a single oral dose ED90 ≤ 10 mg/kg for the 2a analogs (late lead) and an ED90 ≤ 40 mg/kg/day with 1-3 oral doses for the (R)-3a series (early lead), and 2) identify the antimalarial mechanisms of action and resistance of 2a and (R)-3a (or their more potent analogs) by chemoproteomic and resistance-selection approaches, respectively. The ancillary goal of this proposal is to develop structure-activity relationships (SAR) for the P. falciparum gametocytocidal potency and P. berghei liver-stage potency of these two series, and to determine consensus pharmacophores for multi-stage activities (asexual blood-stage potencies plus gametocytocidal and/or liver-stage potencies). Efficacious compounds identified in this way will thus be well-positioned for further preclinical development.