Optimization of antimalarials targeting multiple life stages of the parasite

针对寄生虫多个生命阶段的抗疟药物的优化

• 批准号: 10813425
• 负责人: Paul R Carlier
• 金额: $ 7.59万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-04 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10813425
• 关键词: Address; Adsorption; Affect; Antimalarials; Applications Grants; Artemisinins; Azides; Benzofurans; Biological; Biological Assay; Biological Availability; Blood; Cessation of life; Chemicals; Chemistry; Chloroquine; Clinical; Complement; Consensus; Contracts; Copper; Development; Diazomethane; Disease; Dose; Drug Kinetics; Drug resistance; Escherichia coli; Evolution; Excretory function; Funding; Goals; Growth; Human; In Vitro; Infection; Lead; Libraries; Life; Ligands; Liver; Malaria; Mammalian Cell; Medical; Metabolism; Modification; Molecular Target; Mus; Oral; Oral Administration; Parasite resistance; Parasites; Pharmaceutical Preparations; Phenotype; Plasma; Plasmodium; Plasmodium berghei; Plasmodium falciparum; Population; Populations at Risk; Positioning Attribute; Probability; Property; Proteins; Proteomics; Rattus; Recrudescences; Resistance; Resistance development; Risk; Series; Solubility; Structure; Structure-Activity Relationship; Synthesis Chemistry; Toxic effect; Triage; United States National Institutes of Health; Work; analog; asexual; chemoproteomics; chemotherapeutic agent; drug candidate; experimental study; genome sequencing; improved; in vivo; lead optimization; malaria infection; meter; mouse model; novel; novel therapeutics; parent grant; pathogen; pharmacophore; photolysis; pre-clinical; preclinical development; prevent; resistance mechanism; scaffold; screening; timeline; virtual; whole genome

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.

项目概要/摘要 [家长资助] 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。由于对现有药物的耐药性不断增加，迫切需要 预防和治疗疟疾感染的新药。该资助申请重点关注两个新颖的优化 抗疟药（2a 和 (R)-3a）针对我们之前的研究中出现的寄生虫的多个生命阶段 Malaria Box 化合物 MMV008138 以 apicoplast 为目标。这些化合物是通过组合鉴定的 对包含 500 万种公开化合物的库进行基于原子性质场的虚拟配体筛选 (VLS) 合成化学运动。尽管 2a 和 (R)-3a 与 MMV008138 具有结构相似性并杀死无性生殖 血液阶段，其作用机制独立于顶端质体。此外，而 MMV008138 只影响 无性血液阶段，2a 也杀死 V 阶段配子细胞，(R)-3a 微弱地杀死肝脏阶段的伯氏疟原虫。对于每个 在这两个新型化合物系列中，我们将探索：i) 控制效力、细胞选择性的结构活性关系， 和功效； ii) 控制吸附、分布、代谢和排泄的结构特性关系；和三） 它们的潜在作用机制和抵抗机制。该项目的总体目标是优先考虑临床前线索 具有新颖的作用机制、对疟原虫对人类宿主的高选择性以及理化特性 与口服候选药物的开发相容。 R01 提案的两个主要目标 目的是：1) 对 2a（先导）和 (R)-3a（命中）进行结构修饰，以优化体外无性血液阶段效力 配子细胞和/或肝阶段活性、药物样特性和药代动力学，实现体内伯氏疟原虫- 感染小鼠单次口服剂量 2a 类似物（晚期先导）的 ED90 ≤ 10 mg/kg 和 ED90 ≤ 40 mg/kg/天的疗效 (R)-3a 系列（早期领先）口服 1-3 剂，2) 确定抗疟作用和耐药机制 分别通过化学蛋白质组学和抗性选择方法对 2a 和 (R)-3a（或其更有效的类似物）进行研究。这 该提案的辅助目标是开发恶性疟原虫杀配子细胞的结构-活性关系（SAR） 这两个系列的效力和伯氏疟原虫肝阶段效力，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细胞和/或肝脏阶段效力）。有效化合物 因此，以这种方式确定的药物将为进一步的临床前开发做好准备。

项目成果

Malaria Box-Inspired Discovery of N-Aminoalkyl-β-carboline-3-carboxamides, a Novel Orally Active Class of Antimalarials.

疟疾盒启发发现 N-氨基烷基-β-咔啉-3-甲酰胺，一种新型口服活性抗疟药。

• DOI: 10.1021/acsmedchemlett.1c00663
• 发表时间: 2022
• 期刊: ACS medicinal chemistry letters
• 影响因子: 4.2
• 作者: Mathew,Jopaul;Ding,Sha;Kunz,KevinA;Stacy,EmilyE;Butler,JoshuaH;Haney,ReaganS;Merino,EmilioF;Butschek,GrantJ;Rizopoulos,Zaira;Totrov,Maxim;Cassera,MariaB;Carlier,PaulR
• 通讯作者: Carlier,PaulR