Selective inhibition of tRNA synthetases from pathogenic protozoa

选择性抑制致病性原生动物的 tRNA 合成酶

基本信息

批准号：
8300951
负责人：
WILHELMUS G. J. HOL
金额：
$ 70.43万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8300951
关键词：
Active Sites Address Adopted Adverse effects Affinity African Trypanosomiasis Amino Acids Amino Acyl-tRNA Synthetases Area Binding Binding Sites Biological Biological Assay Catalysis Cells Chagas Disease Chemicals Complex Crystallography Development Disease Drug Delivery Systems Drug Design Drug resistance Enzymes Family Filtration Future Goals Histidine-tRNA Ligase Homologous Gene Host Defense Housing Human Infection Institutes Investigation Knowledge Leishmania Leishmaniasis Libraries Life Ligase Methionine-tRNA Ligase Methodology Methods Molecular Molecular Conformation Molecular Weight Organism Parasites Pathway interactions Patients Pharmaceutical Preparations Preclinical Drug Evaluation Procedures Protein Biosynthesis Proteins Protozoa Research Research Personnel Resistance Screening procedure Series Solutions Specificity Staging Structure System Therapeutic Agents Toxic effect Trypanosoma brucei brucei Trypanosoma cruzi Tyrosine-tRNA Ligase Variant Work adenylate base computational chemistry design drug development experience improved in vitro activity inhibitor/antagonist neglect new therapeutic target novel pathogen public health relevance scaffold small molecule libraries

项目摘要

DESCRIPTION (provided by applicant): This project focuses on essential proteins from three major global pathogenic protozoa, Trypanosoma brucei, Trypanosoma cruzi and Leishmania species. These are related parasites which cause sleeping sickness, Chagas disease, and leishmaniasis, respectively, and are responsible for tens of millions of infections annually, mainly in the tropical and subtropical areas of the world. These sophisticated protozoa are able to avoid the host defense systems, and cause prolonged suffering for the patients. The few drugs that are available have serious side-effects and drug resistance problems are rising. This proposal addresses the need for developing new therapeutics by targeting a critical biological pathway shared by these eukaryotic organisms. This strategy will facilitate drug development across the three protozoa by using the same inhibitor scaffolds. Specifically, three aminoacyl-tRNA synthetase (aaRS) families that are essential for protein synthesis in living cells will be targeted by integrating structure-based and compound library screening methodologies. The approaches include: (i) "piggyback" inhibitor development based on known aaRS inhibitors for other pathogens (some of which inhibit trypanosomatids several orders of magnitude better than human cells), (ii) high throughput solution screening of chemical libraries, (iii) fragment cocktail crystallographically, and (iv) computational chemistry. Compound hits will be subjected to rounds of optimization to improve potency and selectivity by structure-based design. Newly synthesized inhibitors will be evaluated by enzyme and cell-based assays to assess efficacy, selectivity and toxicity. The goal of this project is to arrive at one or two submicromolar inhibitors for five of the aaRS enzymes targeted. These would provide new starting points for subsequent drug development efforts. PUBLIC HEALTH RELEVANCE: The research is directly relevant to the development of therapeutic agents for major, yet largely neglected, diseases occurring in tropical and subtropical areas, threatening hundreds of millions of people. Highly potent compounds that selectively inhibit protein synthesis in pathogenic protozoa will be optimized using structure-based drug design methods.

描述（由申请人提供）：该项目着重于三种主要全球致病原生动物，锥虫锥虫，克鲁氏锥虫和利什曼原虫物种的必需蛋白质。这些是相关的寄生虫，分别引起睡眠疾病，chagas病和利什曼病，并每年造成数千万感染，主要是在世界的热带和亚热带地区。这些复杂的原生动物能够避免宿主防御系统，并为患者造成长时间的痛苦。可用的少数药物具有严重的副作用，耐药性问题正在增加。该建议通过针对这些真核生物共有的关键生物学途径来解决开发新疗法的必要性。该策略将通过使用相同的抑制剂支架来促进三种原生动物的药物开发。具体而言，通过整合基于结构的和复合库筛选方法，将针对活细胞中蛋白质合成至关重要的三个氨基酰基-TRNA合成酶（AARS）家族。这些方法包括：（i）基于其他病原体的已知AARS抑制剂（其中一些抑制锥形抑制剂）的“ Piggyback”抑制剂发育（其中一些抑制锥虫比人类细胞好几个数量级），（ii）化学文库的高吞吐量溶液筛选，（III）碎片鸡尾酒在晶体上，（iv）计算化学。复合命中将受到优化回合，以通过基于结构的设计提高效力和选择性。新合成的抑制剂将通过酶和基于细胞的测定法评估有效性，选择性和毒性。该项目的目的是针对目标的五种AARS酶达到一两个亚旋风抑制剂。这些将为随后的药物开发工作提供新的起点。公共卫生相关性：这项研究与在热带和亚热带地区发生的主要但很大程度上被忽视的主要但很大程度上忽视的治疗剂的开发直接相关，威胁着数亿人。有效抑制致病原生动物中蛋白质合成的高度有效化合物将使用基于结构的药物设计方法进行优化。