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

基于结构的 T. brucei 甲硫氨酰 tRNA 合成酶抑制剂的优化

• 批准号: 8370741
• 负责人: Frederick Simmons Buckner
• 金额: $ 61.14万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8370741
• 关键词: ABCB1 gene; Abbreviations; Acute; Address; Africa South of the Sahara; African Trypanosomiasis; Animals; Area; Back; Binding; Biological Assay; Biological Availability; Biological Testing; Blood - brain barrier anatomy; Canis familiaris; Cell Membrane Permeability; Cells; Chemistry; Collaborations; Complex; Data; Development; Disease; Drug Delivery Systems; Drug Design; Drug Kinetics; Drug resistance; Enzyme Inhibition; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Feedback; Glycoproteins; Goals; Growth; Half-Life; Human; In Vitro; Infection; Inhibitory Concentration 50; Intramuscular; Intravenous; Kidney; Lead; Letters; Liver Microsomes; Mammalian Cell; Melarsoprol; Metabolic; Metabolism; Methionine; Methionine-tRNA Ligase; Modeling; Molecular; Multi-Drug Resistance; Mus; Neuraxis; Oral; Parasites; Parasitic Diseases; Parasitology; Penetration; Permeability; Pharmaceutical Preparations; Pharmacology; Pharmacology and Toxicology; Preclinical Testing; Process; Property; RNA Interference; Research; Resistance; Resistance development; Risk; Scientist; Series; Serum; Site; Solubility; Staging; Step Tests; Structure; Structure-Activity Relationship; Surface; Test Result; Testing; Therapeutic; Toxic effect; Triage; Trypanosoma brucei brucei; Trypanosomiasis; Universities; Urea; Validation; Washington; Work; analog; aqueous; base; chemical genetics; combat; cost; cytotoxicity; design; drug discovery; enzyme activity; experience; feeding; improved; indexing; inhibitor/antagonist; intraperitoneal; iterative design; liquid chromatography mass spectrometry; meetings; neglect; next generation; novel therapeutics; pre-clinical; pressure; resistant strain; scaffold; scale up; stability testing

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.

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一系列来自原生动物寄生虫布鲁氏锥虫的甲硫基tRNA合成酶选择性抑制剂。长期目标是找到治疗由布鲁氏杆菌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：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发现。其中包括：甲硫基tRNA合成酶作为抗布鲁氏菌感染药物靶点的遗传和化学验证；高纳摩尔浓度抑制寄生虫生长化合物的鉴定；发现一种具有口服生物利用度和良好膜通透性的分子支架，具有潜在的中枢神经系统穿透能力；通过与华盛顿大学的霍尔博士合作，研究了目标酶的抑制剂结合晶体结构。拟议的工作将有两个具体目标。目的之一是利用基于结构的设计来指导新一代布鲁氏虾甲硫基tRNA合成酶抑制剂的合成，这些抑制剂在保持选择性和膜通透性的同时提高了效力和代谢稳定性。第二个目的是使用一套完善的生物测定法来评估新合成的化合物的功效、药理学性质和毒性。预先定义的标准将用于通过或不通过每个生物测试的化合物，并且结果将不断反馈到迭代设计过程中。还将审查耐药性的可能性。该项目的目标是确定一种先导化合物和一种备用化合物，为进一步开发进行全面的GLP临床前药理学和毒理学研究做好准备。