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: 10298005
• 负责人: Paul R Carlier
• 金额: $ 76.82万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 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/10298005
• 关键词: Address; Adsorption; Affect; Antimalarials; Applications Grants; Artemisinins; Azides; Benzofurans; 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; Positioning Attribute; Property; Proteins; Proteomics; Rattus; Recrudescences; Resistance; Resistance development; Risk; Series; Solubility; Structure; Structure-Activity Relationship; Synthesis Chemistry; TimeLine; Toxic effect; Triage; United States National Institutes of Health; Ursidae Family; Work; analog; asexual; base; chemoproteomics; chemotherapeutic agent; drug candidate; experimental study; genome sequencing; improved; in vivo; infection risk; lead optimization; malaria infection; mouse model; novel; novel therapeutics; pathogen; pharmacophore; photolysis; pre-clinical; preclinical development; prevent; resistance mechanism; scaffold; screening; virtual; whole genome

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.

项目概要/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 由于对现有药物的耐药性不断增强，面临着感染疟疾的风险。 预防和治疗疟疾感染的新药的医疗需求。 优化两种新型抗疟药（2a 和 (R)-3a）以针对出现的寄生虫的多个生命阶段 来自我们之前针对 apicoplast 的 Malaria Box 化合物 MMV008138 的研究。 使用基于原子属性场的虚拟配体筛选（VLS）的组合来鉴定化合物 包含 500 万个公开化合物和合成化学活动的库。虽然 2a 和 (R)-3a。 与MMV008138结构相似，杀死无性血阶段，其作用机制是 此外，MMV008138 只影响无性血液阶段，而 2a 也会杀死细胞。 V 期配子细胞和 (R)-3a 对两种新型的伯氏疟原虫肝脏阶段都有微弱的杀灭作用。 化合物系列，我们将探索：i) 控制效力、细胞选择性和的结构活性关系 功效；ii) 控制吸收、分布、代谢和排泄的结构特性关系； iii) 他们潜在的行动和抵抗机制 该项目的总体目标是确定优先顺序。 临床前先导药物具有新颖的作用机制、对疟原虫相对于人类宿主的高选择性，以及 与口服候选药物的开发相容的理化特性。 该 R01 提案的主要目标是：1) 结构修改 2a（先导）和 (R)-3a（命中）以优化体外 除了杀配子和/或肝脏阶段活性、药物样特性之外，还具有无性血液阶段效力，以及 药代动力学，单次口服剂量达到伯氏疟原虫感染小鼠体内疗效 ED90 ≤ 10 mg/kg 对于 2a 类似物（晚期先导）和 ED90 ≤ 40 mg/kg/天（R）-3a 系列（早期先导）1-3 次口服剂量， 2) 确定 2a 和 (R)-3a（或其更有效的药物）的抗疟作用机制和耐药性 类似物）分别通过化学蛋白质组学和抗性选择方法。 提案是开发恶性疟原虫杀配子细胞效力的结构-活性关系（SAR） 这两个系列的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）。 因此，以这种方式鉴定的化合物将为进一步的临床前开发做好准备。