Optimization of methionyl-tRNA synthetase inhibitors for human African trypanosomiasis

 描述(由申请人提供)：在这项提案中，来自原生动物寄生虫布氏锥虫的几种有效的甲硫酰-tRNA合成酶抑制剂将进行优化，以实现治疗人类非洲锥虫病的新疗法。这项研究将由华盛顿大学和PATH的科学家组成的一个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。这项拟议的研究是基于在当前筹资期间取得的强劲进展，在此期间获得了多个系列布鲁氏毛滴虫甲硫酰-tRNA合成酶抑制剂，这些药物显示出对寄生虫细胞的纳摩尔效力、对哺乳动物细胞的低毒性、口服和中枢神经系统的可用性，以及在小鼠感染模型中的有效性。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不通过每一次生物测试的化合物，结果将不断反馈到迭代设计过程中。此外，还将检查耐药的可能性。该项目的目标是确定一个临床前候选化合物和一到两个备用化合物，这些化合物可以用于全面的GLP临床前药理学和毒理学研究，以便进一步开发。

 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.