Optimization of antimalarials targeting multiple life stages of the parasite

项目摘要/摘要 疟疾寄生虫是最致命的真核病原体之一，占世界人口的40%以上 有感染疟疾的风险。由于对目前可用的药物的抗药性日益增长，有一个紧迫的问题 医学上需要新药来预防和治疗疟疾感染。这项拨款申请的重点是 两种新型抗疟药(2a和(R)-3a)的优化以针对出现的寄生虫的多个生命阶段 根据我们之前对疟疾盒化合物MMV008138的研究，MMV008138针对的是质膜。这些 使用基于原子性质场的虚拟配体筛选(VLS)的组合来鉴定化合物 拥有500万种可公开获取的化合物和合成化学活动的图书馆。虽然2a和(R)-3a 与MMV008138结构相似，可杀死无性血期，其作用机制为 不依赖于质外体。此外，虽然MMV008138只影响无性血液阶段，但2a也会导致死亡 V期配子体，(R)-3a对伯氏疟原虫肝期有微弱杀灭作用。对于这两部小说中的每一部 化合物系列，我们将探索：i)控制效力、细胞选择性和 功效；ii)控制吸附、分布、新陈代谢和排泄的结构性质关系；以及 三)其潜在的作用和抵抗机制。该项目的首要目标是确定优先顺序 具有新的作用机制、对疟原虫对人类宿主具有高选择性的临床前先导化合物，以及 与口服候选药物的开发相容的物理化学性质。两个人 该R01方案的主要目标是：1)对2a(Lead)和(R)-3a(Hit)进行结构修饰，以在体外进行优化 除了配子细胞和/或肝脏阶段的活动外，无性血液阶段的潜力，类药物的特性，以及 单剂量口服ED90≤10 mg/kg对伯氏肺孢子虫感染小鼠体内药代动力学的影响 对于2a类似物(晚期铅)和ED90≤40 mg/kg/天，1-3次口服剂量用于(R)-3a系列(早期铅)， 2)确定2a和(R)-3a(或其更有效的)的抗疟疾作用机制和抗药性 类似物)，分别通过化学蛋白质组学和抗性选择方法。这样做的辅助目标是 建议开发恶性疟原虫配子体杀伤力的结构-活性关系(SAR)和 伯氏假单胞菌肝期效价的这两个系列，并确定共识的药效团为多阶段 活动(无性血液阶段潜力加上杀配子细胞和/或肝脏阶段潜力)。有效的 因此，以这种方式确定的化合物将为进一步的临床前开发做好准备。

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.