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

基本信息

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
项目类别：
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

项目摘要

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氏锥虫的甲硫氨酰 tRNA 合成酶的选择性抑制剂。长期目标是找到治疗由布氏锥虫感染引起的非洲人类锥虫病的新疗法。该研究将由华盛顿大学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 Dr. Buckner（药理学和寄生虫学）。 Verlinde（基于结构的药物设计）。拟议的研究基于几个关键的初步发现。其中包括：甲硫氨酰 tRNA 合成酶作为对抗布氏锥虫感染的药物靶点的遗传和化学验证；鉴定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，该支架具有口服生物利用度和优异的膜渗透性，具有潜在的中枢神经系统渗透能力；通过与华盛顿大学的 Hol 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。一个目标是使用基于结构的设计来指导下一代布氏甲硫氨酰 tRNA 合成酶抑制剂的合成，以提高效力和代谢稳定性，同时保留选择性和膜通透性。第二个目标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、药理学特性和毒性。预定义的标准将用于通过或失败每个生物测试的化合物，结果将不断反馈到迭代设计过程中。还将检查耐药性的可能性。该项目的目标是确定一种先导化合物和一种备用化合物，为全面的 GLP 临床前药理学和毒理学研究做好准备，以供进一步开发。公共卫生相关性：非洲人类锥虫病是一种很大程度上被忽视的寄生虫病，在撒哈拉以南非洲地区最为流行，使超过 6000 万人面临风险。该提案直接解决了治疗该疾病的更有效、成本更低、毒性更小的药物的需求。