Discovery of long-acting, chemoprotective antimalarial compounds

发现长效、化学保护性抗疟化合物

基本信息

批准号：
10580781
负责人：
Elizabeth A Winzeler
金额：
$ 69.33万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-25 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10580781
关键词：
ADME Study Acetyl Coenzyme A Amino Acyl-tRNA Synthetases Anemia Animal Model Animals Antimalarials Binding Proteins Biological Assay Blood Cell Culture Techniques Cells Cerebral Malaria Cessation of life Chemoprevention Chemoprophylaxis Chemoprotective Agent Clinical Clinical Trials Cluster Analysis Culicidae Data Set Development Dihydrofolate Reductase Dihydroorotate dehydrogenase Disease Drug Design Drug Kinetics Drug resistance Erythrocytes Evolution Family Genomics Goals Human In Vitro Infection Injectable International Intramuscular Injections Investigation Liver Luciferases Malaria Malaria prevention Medicine Metabolic Methods Microsomes Military Personnel Mitochondria Oral Parasite resistance Parasites Parasitology Patients Persons Pharmaceutical Preparations Phenotype Phosphotransferases Plasmodium Plasmodium falciparum Plasmodium vivax Population Prodrugs Prophylactic treatment Proteins Proteomics Public Health Research Personnel Series Severities Structure Testing Therapeutic antibodies Toxic effect Travel Work animal efficacy asexual base clinical candidate design drug development efficacy testing genome analysis inhibitor large datasets lead optimization malaria infection meter model organism mouse model next generation novel predictive modeling predictive test prevent prophylactic scaffold screening small molecule symptom treatment therapy development tool vaccine-induced antibodies whole genome

项目摘要

ABSTRACT To discover leads for next-generation chemoprotective antimalarial drugs, we tested >500,000 compounds for their ability to inhibit liver-stage development of luciferase-expressing Plasmodium parasites (681 with an IC50 < 1 µM). Cluster analysis identified potent and previously unreported scaffold families as well as other series previously associated with chemoprophylaxis. Further testing through multiple phenotypic assays that predict stage-specific and multispecies antimalarial activity revealed compound classes that are likely to provide symptomatic relief from blood-stage and others that only prevent malaria. Target identification using functional assays, in vitro evolution or metabolic profiling of the most potent blood stage-active scaffolds revealed multiple mitochondrial inhibitors but also compounds with likely new mechanisms of action. The total dataset provided hundreds of new chemotypes and scaffold families (compounds sharing a core structure) that may be used in further drug development for the treatment and prevention of malaria. Here we propose to perform hit to lead optimization on 1-2 scaffold families per year, synthesizing approximately ~750 compounds. Select compounds (10%) will be tested for microsomal stability, protein binding, hERG, and CYP inhibition. Pharmacokinetic and prophylactic animal model testing will be performed on ~10 compounds per year. In addition, we will explore whether promising leads can be converted to a prodrug form that can be given as intramuscular injection which provides long- lasting chemoprevention. Hit to lead optimization will be accompanied by investigation into the mechanism of action of six scaffold families using a suite of different methods including in vitro evolution and whole genome analysis. We aim to develop treatments that may prevent malaria from developing, that are convenient to use and which are superior to current medicines. .

抽象的为了发现下一代化学保护性抗疟药物的先导化合物，我们测试了超过 500,000 种化合物第 681 章 IC50 < 1 µM）。聚类分析鉴定出有效且之前未报道的支架家族。先前与化学预防相关的其他系列通过多种表型进行了进一步测试。预测阶段特异性和多物种抗疟活性的测定揭示了化合物类别可能会缓解血液阶段的症状，而其他药物只能预防疟疾。使用功能测定、体外进化或代谢分析最有效的血液进行鉴定阶段活性支架揭示了多种线粒体抑制剂，但也发现了可能具有新功能的化合物整个数据集提供了数百种新的化学型和支架家族。（共享核心结构的化合物）可用于进一步药物开发以治疗和在这里，我们建议对每个 1-2 个支架家族进行命中先导优化。年，将测试合成大约 750 种化合物（10%）。微粒体稳定性、蛋白质结合、hERG 和 CYP 抑制。此外，我们将每年对约 10 种化合物进行模型测试。引线可以转化为前药形式，可以作为肌肉注射给予，从而提供长效作用。持久的化学预防将伴随着对先导化合物优化的机制研究。使用一系列不同的方法（包括体外进化和整体）对六个支架家族的作用进行了研究我们的目标是开发可以预防疟疾的治疗方法，即使用方便，优于现有药物。。