Developing methionyl tRNA synthetase inhibitors as therapeutics for Chagas disease

开发甲硫氨酰 tRNA 合成酶抑制剂作为恰加斯病的治疗药物

• 批准号: 10132983
• 负责人: Frederick Simmons Buckner
• 金额: $ 73.36万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10132983
• 关键词: Abbreviations; Acute; Address; Affect; African Trypanosomiasis; Ames Assay; Animals; Area Under Curve; Back; Binding Proteins; Binding Sites; Biological Assay; Blood; Cell Line; Cells; Cellular Assay; Cessation of life; Chagas Disease; Chemicals; Chronic; Cytochrome P450; Data; Development; Disease; Dose; Drug Kinetics; Enzyme Inhibitor Drugs; Enzymes; Ethers; Etiology; Funding; Genes; Goals; Growth; Heart; Human; Individual; Indoles; Infection; Intestines; Intravenous; Investigational Drugs; Knowledge; Latin America; Lead; Libraries; Mammalian Cell; Maximum Tolerated Dose; Methionine; Methionine-tRNA Ligase; Micronucleus Tests; Microsomes; Mitochondria; Mitochondrial Proteins; Modeling; Mus; Neuraxis; Octanes; Oral; Oral cavity; Parasitemia; Parasites; Parasitic Diseases; Partition Coefficient; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology and Toxicology; Process; Property; Protein Biosynthesis; Rattus; Research; Research Contracts; Safety; Signal Transduction; Solubility; Structure; Structure-Activity Relationship; System; Testing; Therapeutic; Toxic effect; Toxicology; Trypanosoma; Trypanosoma cruzi; United States National Institutes of Health; Variant; Water; Work; analog; base; cytotoxicity; design; drug candidate; fetal bovine serum; genotoxicity; good laboratory practice; in vitro Assay; in vivo imaging system; indexing; inhibitor/antagonist; iterative design; lead candidate; lead optimization; liquid chromatography mass spectrometry; mouse model; nanomolar; novel therapeutics; pre-clinical; preclinical study; prevent; process optimization; receptor; safety study; scaffold; screening; success

Project Summary In this project, inhibitors of the enzyme methionyl-tRNA synthetase from the protozoan parasite Trypanosoma cruzi will be optimized to develop new drug candidates for Chagas disease. The available treatments for Chagas disease are highly toxic and not fully efficacious, especially for the chronic stage. They need to be replaced with safer and more effective drugs to treat the millions of people, mainly in Latin America, afflicted by Chagas disease. The proposed research is based on the strong preliminary data of methionyl-tRNA synthetase inhibitors from multiple chemical scaffolds showing nanomolar potency against T. cruzi cells, low toxicity to mammalian cells, oral availability, and potent activity in murine infection models. We have chosen two chemical scaffolds for lead optimization. Pre-defined criteria will be used to advance compounds through a rigorous screening cascade, and the results will continually be fed back into the iterative design and synthesis process. The goal for this project is to identify one preclinical candidate and at least one backup compound that are ready for comprehensive GLP preclinical pharmacology and toxicology studies for further development.

项目总结