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

描述(申请人提供)：在这项提案中，将使用基于结构的药物设计方法来优化一系列来自原生动物寄生虫布鲁氏锥虫的甲硫酰tRNA合成酶的选择性抑制剂。长期目标是找到治疗由布氏旋毛虫感染引起的非洲人类锥虫病的新疗法。这项研究将由华盛顿大学一个经验丰富的研究团队进行，该团队由四名科学家组成：范博士(化学)、巴克纳博士(药理学和寄生虫学)、盖尔布博士(药理学和化学)和弗林德博士(基于结构的药物设计)。这项拟议的研究是基于几个关键的初步发现。这些进展包括：从遗传学和化学角度验证甲硫酰tRNA合成酶作为抗布氏毛滴虫感染药物靶点的可行性；鉴定出在高纳米摩尔浓度范围内抑制寄生虫生长的化合物；发现一种具有口服生物利用度和良好的膜渗透性的分子支架，该支架具有潜在的中枢神经系统穿透能力；以及通过与华盛顿大学的霍尔博士合作，发现目标酶与抑制剂结合的晶体结构。拟议的工作将有两个具体目标。一个目标是使用基于结构的设计来指导合成下一代布鲁氏菌甲硫酰tRNA合成酶抑制剂，在保持选择性和膜通透性的同时，提高效力和代谢稳定性。第二个目标是使用一套成熟的生物测试方法来评估新合成的化合物的有效性、药理特性和毒性。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种先导化合物和一种后备化合物，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。 公共卫生意义：非洲人类锥虫病是一种在很大程度上被忽视的寄生虫病，在撒哈拉以南非洲最为流行，使6000多万人处于危险之中。这项建议直接解决了治疗这种疾病的更有效、更低成本和毒性更低的药物的需求。

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. PUBLIC HEALTH RELEVANCE: Human African trypanosomiasis is a largely neglected parasitic disease most prevalent in sub-Saharan Africa and putting more than 60 million people at risk. This proposal directly addresses the need of more effective, low cost, and less toxic drugs for treating the disease.