Structures and selective inhibition of tRNA synthetases from pathogenic protozoa

致病性原生动物 tRNA 合成酶的结构和选择性抑制

• 批准号: 7934796
• 负责人: WILHELMUS G. J. HOL
• 金额: $ 73.2万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-28 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7934796
• 关键词: Active Sites; Address; Adopted; Adverse effects; Affinity; African Trypanosomiasis; Amino Acyl-tRNA Synthetases; Area; Binding; Binding Sites; Biological; Biological Assay; Catalysis; Cells; Cessation of life; Chagas Disease; Chemicals; Complex; Development; Disease; Drug Delivery Systems; Drug resistance; Enzymes; Family; Filtration; Future; Goals; Homologous Gene; Host Defense; Housing; Human; Infection; Institutes; Investigation; Knowledge; Leishmania; Leishmaniasis; Libraries; Life; 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; Variant; Work; abstracting; adduct; adenylate; base; computational chemistry; design; drug development; experience; improved; in vitro Assay; inhibitor/antagonist; neglect; new therapeutic target; novel; pathogen; scaffold; small molecule libraries

Abstract: 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 millions of infections and nearly one million deaths 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.

摘要： 该项目的重点是从三个主要的全球致病性 原生动物、布氏锥虫、克氏锥虫和利什曼原虫种。这些是 引起昏睡病、恰加斯病和利什曼病的相关寄生虫， 分别造成数百万感染和近100万死亡 每年，主要在世界的热带和亚热带地区。这些复杂 原生动物能够避开宿主的防御系统，并造成长期的痛苦， 病人现有的几种药物有严重的副作用， 抵抗问题正在增加。该提案涉及开发新的 通过靶向这些真核生物共享的关键生物学途径， 有机体这一策略将通过以下方式促进跨越三种原生动物的药物开发： 使用相同的抑制剂支架。 具体而言，三个氨酰-tRNA合成酶（阿尔斯）家族是必需的， 活细胞中蛋白质合成的目标将是通过整合基于结构的， 化合物库筛选方法。这些方法包括：（一）“搭载” 基于已知的用于其他病原体的阿尔斯抑制剂的抑制剂开发（一些 其比人细胞更好地抑制锥虫几个数量级），（ii） 化学文库的高通量溶液筛选，（iii）片段混合物 晶体学，和（iv）计算化学。复合命中将受到 通过基于结构的设计进行多轮优化以提高效力和选择性。 新合成的抑制剂将通过酶和基于细胞的测定进行评价， 评估疗效、选择性和毒性。这个项目的目标是达到一两个 亚微摩尔抑制剂的五个阿尔斯酶的目标。这些将提供 为后续药物开发工作提供新的起点。