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）：在这种基于结构的药物设计方法中，将使用原生动物寄生虫Brucei的一系列选择性抑制剂来优化蛋白酶甲基TRNA合成酶的一系列选择性抑制剂。长期的目标是达到新的治疗药物，以治疗由T. brucei感染引起的非洲人类锥虫病。这项研究将由华盛顿大学经验丰富的研究团队进行，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）。拟议的研究基于几个关键的初步发现。其中包括：甲基tRNA合成酶的遗传和化学验证是针对布鲁氏菌感染的药物靶标；鉴定抑制寄生虫生长高纳摩尔浓度的化合物；发现了一个分子支架，该支架表现出口服生物利用度和出色的膜渗透性，并具有潜在的中枢神经系统穿透性；通过与华盛顿大学Hol博士的合作，目标酶的抑制剂结合晶体结构。拟议的工作将有两个具体的目标。一个目的是利用基于结构的设计来指导t. brucei甲二烯基TRNA合成酶的下一代抑制剂的合成，具有提高的效力和代谢稳定性，同时保持选择性和膜渗透性。第二个目的是使用一组良好的生物学测定法来评估新合成的化合物，以疗效，药理特性和毒性评估。预定义的标准将用于将每个生物测试的化合物传递或失效化合物，并且结果将不断地回到迭代设计过程中。还将检查耐药性的潜力。该项目的目标是确定一个铅和一种备用化合物，这些铅和备用化合物准备进行全面的GLP临床前药理学和毒理学研究，以进行进一步发展。公共卫生相关性：非洲人类锥虫病是一种在撒哈拉以南非洲最普遍的很大程度上被忽视的寄生疾病，并使超过6000万人处于危险之中。该提案直接解决了需要更有效，低成本和毒性较小的药物来治疗该疾病的需求。