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]

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