Optimization of methionyl-tRNA synthetase inhibitors for human African trypanosomiasis

 描述（由申请人提供）：在该提案中，将优化原生动物寄生虫布氏锥虫的甲硫氨酰-tRNA合成酶的几个系列的有效抑制剂，其长期目标是获得治疗人类非洲锥虫病的新疗法。该研究将由华盛顿大学和PATH的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，药理学，毒理学和临床前测试。拟议的研究是基于在当前资助期间取得的重大进展，其中多个系列的T。获得的布氏甲硫氨酰-tRNA合成酶抑制剂显示出抗寄生虫细胞的纳摩尔效力、对哺乳动物细胞的低毒性、口服和CNS可用性以及在鼠感染模型中的功效。拟议的工作将有四个具体目标。预定义的标准将用于通过或失败的化合物来到每个生物学测试，结果将不断反馈到迭代设计过程。还将检查耐药性的可能性。本项目的目标是确定一种临床前候选化合物和一到两种备用化合物，这些化合物可用于全面的GLP临床前药理学和毒理学研究，以供进一步开发。

 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.