Optimization of methionyl-tRNA synthetase inhibitors for human African trypanosomiasis

非洲人锥虫病甲硫氨酰-tRNA合成酶抑制剂的优化

基本信息

批准号：
9217544
负责人：
Frederick Simmons Buckner
金额：
$ 70.96万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9217544
关键词：
Address Africa South of the Sahara African Trypanosomiasis Back Biological Assay Biological Availability Biological Testing Brain Cells Chemicals Data Development Disease Dose Drug Design Drug Kinetics Drug resistance Enzymatic Biochemistry Enzyme Inhibition Enzyme Inhibitor Drugs Enzymes Funding Future Goals Grant Growth Human In Vitro Infection Lead Mammalian Cell Maximum Tolerated Dose Methionine-tRNA Ligase Methods Modeling Modification Molecular Mus Neuraxis Oral Parasite resistance Parasites Parasitic Diseases Parasitology Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Pharmacology Pharmacology and Toxicology Positioning Attribute Preclinical Testing Process Rattus Research Resistance Risk Rodent Safety Scientist Series Signal Transduction Structure Test Result Testing Therapeutic Toxic effect Toxicology Trypanosoma brucei brucei Tumor stage Universities Washington Work analog base candidate selection cost cytotoxicity design drug discovery efficacy study experience fitness genome sequencing in vitro Assay in vivo inhibitor/antagonist iterative design meetings member mouse model nanomolar neglect novel therapeutics pre-clinical preclinical development public health relevance receptor resistance mechanism safety study uptake whole genome

项目摘要

DESCRIPTION (provided by applicant): In this proposal several series of potent inhibitors of the enzyme methionyl-tRNA synthetase from the protozoan parasite Trypanosoma brucei will be optimized with long term goals to arrive at new therapeutics for treating human African trypanosomiasis. The research will be carried out by a highly experienced team formed by scientists at the University of Washington and PATH with expertise covering: structure-based drug design, medicinal chemistry, parasitology, pharmacology, toxicology, and preclinical testing. The proposed research is based on the strong progress made during the current funding period where multiple series of T. brucei methionyl-tRNA synthetase inhibitors were obtained that showed nanomolar potency against parasite cells, low toxicity to mammalian cells, oral and CNS availability, and efficacy in murine infection models. The proposed work will have four specific aims. Pre-defined criteria will be used to pass or fail compounds coming to each biological test, and the results will continually be fed back into the iterative design process. Th potential for drug resistance will also be examined. The goal for this project is to identify one preclinical candidate and one to two backup compounds that are ready for comprehensive GLP preclinical pharmacology and toxicology studies for further development.

描述（由申请人提供）：在本提案中，将对来自原生动物寄生虫布氏锥虫的甲硫氨酰-tRNA合成酶的多个系列的有效抑制剂进行优化，以达到治疗人类非洲锥虫病的新疗法的长期目标。该研究由华盛顿大学和 PATH 科学家组成的经验丰富的团队进行，其专业知识涵盖：基于结构的药物设计、药物化学、寄生虫学、拟议的研究基于当前资助期间取得的重大进展，其中获得了多个系列的布氏锥虫甲硫氨酰-tRNA合成酶抑制剂，这些抑制剂对寄生虫细胞具有纳摩尔级的效力，对哺乳动物细胞的毒性低。、口服和中枢神经系统的可用性以及在小鼠感染模型中的功效拟议的工作将有四个具体目标，将用于通过或失败每个生物测试的化合物，并且将不断提供结果。该项目的目标是确定一种临床前候选药物和一到两种备用化合物，以便进行全面的 GLP 临床前药理学和毒理学研究，以供进一步开发。