Structure-based Optimization of T. brucei methionyl tRNA Synthetase Inhibitors

描述（由申请人提供）：在本提案中，基于结构的药物设计方法将用于优化原生动物寄生虫布氏锥虫甲硫氨酰tRNA合成酶的一系列选择性抑制剂。长期目标是找到治疗由锥虫引起的人类非洲锥虫病的新疗法。布氏杆菌感染这项研究将由华盛顿大学一个经验丰富的研究团队进行，该团队由四位科学家组成：Fan博士（化学）、Buckner博士（药理学和寄生虫学）、Gelb博士（药理学和化学）和Verlinde博士（基于结构的药物设计）。拟议的研究是基于几个关键的初步调查结果。这些包括：甲硫氨酰tRNA合成酶作为抗T.布鲁氏菌感染;通过与华盛顿大学的Hol博士的合作，鉴定了在高纳摩尔浓度下抑制寄生虫生长的化合物;发现了一种分子支架，该分子支架证明了口服生物利用度和优异的膜渗透性，具有潜在的CNS渗透性;以及靶酶的底物结合晶体结构。拟议的工作将有两个具体目标。目的之一是使用基于结构的设计来指导下一代T抑制剂的合成。具有改进的效力和代谢稳定性同时保持选择性和膜渗透性的布鲁氏菌甲硫氨酰tRNA合成酶。第二个目标是使用一套完善的生物测定来评估新合成的化合物的功效，药理学性质和毒性。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先导化合物和一种备用化合物，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 structure-based drug design approaches will be used to optimize a series of selective inhibitors of the enzyme methionyl tRNA synthetase from the protozoan parasite Trypanosoma brucei. The long term goal is to arrive at new therapeutics for treating human African trypanosomiasis caused by T. brucei infection. The research will be carried out by a highly experienced research team at the University of Washington consisting of four scientists: Dr. Fan (chemistry), Dr. Buckner (pharmacology and parasitology), Dr. Gelb (pharmacology and chemistry), and Dr. Verlinde (structure-based drug design). The proposed research is based on several key preliminary findings. These include: genetic and chemical validation of methionyl tRNA synthetase as a drug target against T. brucei infection; identification of compounds that inhibit parasite growth a high-nanomolar concentrations; discovery of a molecular scaffold that demonstrates oral bioavailability and excellent membrane permeability with potentially CNS penetration; and inhibitor-bound crystal structures of the target enzyme through collaboration with Dr. Hol at the University of Washington. The proposed work will have two specific aims. One aim is to use structure-based design to guide synthesis of next generation inhibitors of T. brucei methionyl tRNA synthetase with improved potency and metabolic stability while preserving selectivity and membrane permeability. The second aim is to use a set of well-established biological assays to evaluate the newly synthesized compounds in terms of efficacy, pharmacological properties, and toxicity. 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 lead and one backup compound that are ready for comprehensive GLP preclinical pharmacology and toxicology studies for further development.