Developing methionyl tRNA synthetase inhibitors as therapeutics for Chagas disease

项目摘要 在这个项目中，来自原生动物寄生虫锥虫的甲硫酰-tRNA合成酶的抑制剂 将对CRUZI进行优化，以开发治疗恰加斯病的新候选药物。可用的治疗方法 恰加斯病毒性很强，不是完全有效的，特别是对慢性病阶段。他们需要是 取而代之的是更安全、更有效的药物来治疗数百万人，主要是在拉丁美洲， 恰加斯病。提出的研究是基于甲硫酰-tRNA合成酶的强大初步数据。 来自多种化学支架的抑制剂对克氏毛滴虫细胞显示出纳摩尔效力，对 小鼠感染模型中的哺乳动物细胞、口服利用度和有效活性。我们选择了两个 用于铅优化的化学支架。将使用预定义的标准来推进化合物通过 严格的筛选级联，结果将不断反馈到迭代设计和综合中 进程。该项目的目标是确定一个临床前候选化合物和至少一个后备化合物 为进一步的GLP临床前药理学和毒理学研究做好准备 发展。

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.