Developing methionyl tRNA synthetase inhibitors as therapeutics for Chagas disease

开发甲硫氨酰 tRNA 合成酶抑制剂作为恰加斯病的治疗药物

基本信息

批准号：
10372125
负责人：
Frederick Simmons Buckner
金额：
$ 77.21万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10372125
关键词：
Abbreviations Acute Address Affect African Trypanosomiasis Ames Assay Animals Area Under Curve Back Binding Proteins Binding Sites Biological Assay Blood Cell Line Cells Cellular Assay Cessation of life Chagas Disease Chemicals Chronic Cytochrome P450 Data Development Disease Dose Drug Kinetics Enzyme Inhibitor Drugs Enzymes Ethers Etiology Funding Genes Goals Growth Heart Human Individual Indoles Infection Intestines Intravenous Investigational Drugs Knowledge Latin America Lead Libraries Mammalian Cell Maximum Tolerated Dose Methionine Methionine-tRNA Ligase Micronucleus Tests Microsomes Mitochondria Mitochondrial Proteins Modeling Mus Neuraxis Octanes Oral Oral cavity Parasitemia Parasites Parasitic Diseases Partition Coefficient Pathway interactions Persons Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology and Toxicology Process Property Protein Biosynthesis Rattus Research Research Contracts Safety Signal Transduction Solubility Structure-Activity Relationship System Testing Therapeutic Toxic effect Toxicology Trypanosoma Trypanosoma cruzi United States National Institutes of Health Variant Water Work analog base cytotoxicity design drug candidate fetal bovine serum genotoxicity good laboratory practice in vitro Assay in vivo imaging system indexing inhibitor iterative design lead candidate lead optimization liquid chromatography mass spectrometry mouse model nanomolar novel therapeutics pre-clinical preclinical study prevent process optimization receptor safety study scaffold screening success

项目摘要

Project Summary In this project, inhibitors of the enzyme methionyl-tRNA synthetase from the protozoan parasite Trypanosoma cruzi will be optimized to develop new drug candidates for Chagas disease. The available treatments for Chagas disease are highly toxic and not fully efficacious, especially for the chronic stage. They need to be replaced with safer and more effective drugs to treat the millions of people, mainly in Latin America, afflicted by Chagas disease. The proposed research is based on the strong preliminary data of methionyl-tRNA synthetase inhibitors from multiple chemical scaffolds showing nanomolar potency against T. cruzi cells, low toxicity to mammalian cells, oral availability, and potent activity in murine infection models. We have chosen two chemical scaffolds for lead optimization. Pre-defined criteria will be used to advance compounds through a rigorous screening cascade, and the results will continually be fed back into the iterative design and synthesis process. The goal for this project is to identify one preclinical candidate and at least one backup compound that are ready for comprehensive GLP preclinical pharmacology and toxicology studies for further development.

项目摘要在这个项目中，原生动物寄生虫锥虫菌群的蛋白基-TRNA合成酶的抑制剂 Cruzi将被优化，以开发新毒品的Chagas疾病。可用的治疗 Chagas病具有剧毒，没有完全有效，尤其是在慢性阶段。他们需要取而代之查加斯病。拟议的研究基于蛋白质基-TRNA合成酶的强烈初步数据来自多个化学支架的抑制剂，表明针对克鲁齐细胞的纳摩尔效力，低毒性哺乳动物细胞，口服可用性和鼠类感染模型中的有效活性。我们选择了两个化学支架用于铅优化。预定义的标准将用于通过严格的筛选级联反应，结果将不断馈入迭代设计和合成过程。该项目的目标是确定一个临床前候选者和至少一个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，以进一步发展。