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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

基本信息

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
项目类别：
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

项目摘要

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.

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