Optimization of antimalarials targeting multiple life stages of the parasite

项目概要/摘要[母基金] 疟疾寄生虫是最致命的真核病原体之一，世界上超过40%的人口处于危险之中 感染疟疾由于对目前可用药物的耐药性不断增加，迫切需要以下药物： 预防和治疗疟疾感染的新药。这项拨款申请的重点是两个新的优化 抗疟药（2a和（R）-3a），以靶向从我们以前的工作中出现的寄生虫的多个生命阶段。 靶向顶质体的疟疾盒化合物MMV 008138。这些化合物是使用以下组合鉴定的： 基于原子性质场的虚拟配体筛选（VLS）的500万个公开可用的化合物库， 合成化学运动。尽管2a和（R）-3a与MMV 008138具有结构相似性， 血液阶段，其作用机制是独立的顶质体。此外，MMV 008138仅影响 2a也杀死V期配子体，（R）-3a微弱地杀死伯氏疟原虫肝期。为每个 在这两个新的化合物系列中，我们将探索：i）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） 它们的潜在作用机制和抗性。本项目的总体目标是优先考虑临床前线索 具有新的作用机制、对疟原虫相对于人类宿主的高选择性和物理化学性质， 其与口服可利用的候选药物的开发相容。R 01提案的两个主要目标 1）在结构上修饰2a（先导）和（R）-3a（命中）以优化体外无性血液阶段效力， 配子体和/或肝脏阶段活性、药物样性质和药代动力学，实现体内伯氏疟原虫- 2a类似物（晚期先导化合物）单次经口给药ED 90 ≤ 10 mg/kg和ED 90 ≤ 40 mg/kg/天的感染小鼠疗效 （R）-3a系列口服1-3剂（早期先导），2）确定抗疟作用和耐药性机制 2a和（R）-3a（或其更有效的类似物）的化学蛋白质组学和抗性选择方法。的 该建议的辅助目标是开发恶性疟原虫配子体杀伤剂的结构-活性关系（SAR 效力和伯氏疟原虫肝脏阶段的效力，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）。有效化合物 因此，以这种方式鉴定的基因将很好地定位于进一步的临床前开发。

PROJECT SUMMARY/ABSTRACT [Parent grant] 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 physicochemical 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 gametocitocydal 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.