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

• 批准号: 8489253
• 负责人: WILHELMUS G. J. HOL
• 金额: $ 65.2万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 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/8489253
• 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 Design; Drug Targeting; 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; 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; screening; small molecule libraries

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.

描述（由申请人提供）：该项目重点关注全球三种主要致病原生动物：布氏锥虫、克氏锥虫和利什曼原虫的必需蛋白质。这些是相关的寄生虫，分别引起昏睡病、恰加斯病和利什曼病，每年导致数千万例感染，主要发生在世界热带和亚热带地区。这些复杂的原生动物能够避开宿主的防御系统，给患者带来长期的痛苦。现有的少数药物具有严重的副作用，耐药性问题日益严重。该提案解决了通过针对这些真核生物共享的关键生物途径开发新疗法的需求。该策略将通过使用相同的抑制剂支架促进三种原生动物的药物开发。 具体来说，将通过整合基于结构的化合物库筛选方法来靶向活细胞中蛋白质合成所必需的三个氨酰基-tRNA合成酶（aaRS）家族。这些方法包括：(i) 基于已知的 aaRS 抑制剂开发其他病原体的“搭载”抑制剂（其中一些对锥虫的抑制效果比人类细胞好几个数量级），(ii) 化学文库的高通量溶液筛选，(iii) 晶体碎片鸡尾酒，以及 (iv) 计算化学。化合物命中将经过多轮优化，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基于酶和细胞的测定进行评估，以评估功效、选择性和毒性。该项目的目标是针对五种 aaRS 目标酶找到一种或两种亚微摩尔抑制剂。这些将为后续的药物研发工作提供新的起点。