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.

项目摘要/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40%以上的人口处于危险之中 感染疟疾的风险。由于对现有药物的抗药性日益增强，医学上迫切需要 预防和治疗疟疾感染的新药。这项拨款申请的重点是优化两部小说 抗疟药(2a和(R)-3a)靶向寄生虫的多个生命阶段，这些寄生虫是我们以前在 疟疾盒化合物MMV008138，靶向质外体。这些化合物是用一系列化合物组合鉴定的 基于原子属性场的虚拟配体筛选(VLS)，该库包含500万个公开可用的化合物和 合成化学运动。尽管2a和(R)-3a在结构上与MMV008138相似，并杀死无性系 在血液期，它们的作用机制独立于质外体。此外，鉴于MMV008138仅影响 无性血阶段，2a也杀死V期配子细胞，而(R)-3a弱杀死伯氏疟原虫肝脏阶段。对于每个 在这两个新化合物系列中，我们将探索：i)控制效力、细胞选择性、 和功效；ii)支配吸附、分布、新陈代谢和排泄的结构性质关系；以及iii) 它们潜在的作用和抵抗机制。这个项目的首要目标是确定临床前线索的优先顺序。 具有新的作用机制、对疟原虫对人类宿主的高选择性和物理化学性质 与口服给药候选药物的开发相兼容。本R01提案的两个主要目标 目的是：1)对2a(铅)和(R)-3a(HIT)进行结构修饰，以优化体外无性血期潜力 配子细胞和/或肝脏阶段的活性、类药物特性和药代动力学，在体内实现了P.berghei- 2a类似物(晚期铅)单次口服ED90≤10 mg/kg和ED90≤40 mg/kg/d感染小鼠的疗效 口服1-3剂量的(R)-3a系列(早期铅)，以及2)确定抗疟疾的作用机制和耐药性 2a和(R)-3a(或其更有效的类似物)分别通过化学蛋白质组学和抗性选择方法获得。这个 这项提议的辅助目标是发展恶性疟原虫杀配子细胞的结构-活性关系(SAR)。 这两个系列的效价和伯氏假单胞菌的肝期效价，并确定多阶段的共识药效团 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奠定良好的基础。

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