Lindsay B. Tulloch, Hugh Tawell, Annie E. Taylor, Marta Lopes Lima, Alice Dawson, Sandra Carvalho, Richard J. Wall, Victoriano Corpas-Lopez, Gourav Dey, Jack Duggan, Luma Godoy Magalhaes, Leah S. Torrie, Laura Frame, David Robinson, Stephen Patterson, Michele Tinti, George W. Weaver, William J. Robinson, Monica Cal, Marcel Kaiser, Pascal Mäser, Peter Sjö, Benjamin Perry, John M. Kelly, Amanda Fortes Francisco, Avninder S. Bhambra, Susan Wyllie
{"title":"靶向赖氨酸- trna合成酶的抗锥虫喹唑啉类药物在急性恰加斯病小鼠模型中显示出部分疗效","authors":"Lindsay B. Tulloch, Hugh Tawell, Annie E. Taylor, Marta Lopes Lima, Alice Dawson, Sandra Carvalho, Richard J. Wall, Victoriano Corpas-Lopez, Gourav Dey, Jack Duggan, Luma Godoy Magalhaes, Leah S. Torrie, Laura Frame, David Robinson, Stephen Patterson, Michele Tinti, George W. Weaver, William J. Robinson, Monica Cal, Marcel Kaiser, Pascal Mäser, Peter Sjö, Benjamin Perry, John M. Kelly, Amanda Fortes Francisco, Avninder S. Bhambra, Susan Wyllie","doi":"10.1126/scitranslmed.adu4564","DOIUrl":null,"url":null,"abstract":"<div >The protozoan parasite <i>Trypanosoma cruzi</i> causes Chagas disease, which is among the deadliest parasitic infections in Latin America. Current therapies are toxic and lack efficacy against the chronic stage of infection; thus, new drugs are urgently needed. Here, we describe a previously unidentified series of quinazoline compounds with potential against <i>Trypanosoma cruzi</i> and the related trypanosomatid parasites <i>Trypanosoma brucei</i> and <i>Leishmania donovani</i>. We demonstrated partial efficacy of a lead quinazoline compound in a mouse model of acute Chagas disease. Mechanism of action studies using several orthogonal approaches showed that this quinazoline compound series targeted the ATP-binding pocket of <i>T. cruzi</i> lysyl-tRNA synthetase 1 (KRS1). A high-resolution crystal structure of KRS1 bound to the drug indicated binding interactions that led to KRS1 inhibition. Our study identified KRS1 as a druggable target for treating <i>T. cruzi</i> infection in a mouse model. This quinazoline series shows potential for treating Chagas disease but will require further development to become a future treatment for this neglected disease.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 806","pages":""},"PeriodicalIF":14.6000,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Antitrypanosomal quinazolines targeting lysyl-tRNA synthetase show partial efficacy in a mouse model of acute Chagas disease\",\"authors\":\"Lindsay B. Tulloch, Hugh Tawell, Annie E. Taylor, Marta Lopes Lima, Alice Dawson, Sandra Carvalho, Richard J. Wall, Victoriano Corpas-Lopez, Gourav Dey, Jack Duggan, Luma Godoy Magalhaes, Leah S. Torrie, Laura Frame, David Robinson, Stephen Patterson, Michele Tinti, George W. Weaver, William J. Robinson, Monica Cal, Marcel Kaiser, Pascal Mäser, Peter Sjö, Benjamin Perry, John M. Kelly, Amanda Fortes Francisco, Avninder S. Bhambra, Susan Wyllie\",\"doi\":\"10.1126/scitranslmed.adu4564\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div >The protozoan parasite <i>Trypanosoma cruzi</i> causes Chagas disease, which is among the deadliest parasitic infections in Latin America. Current therapies are toxic and lack efficacy against the chronic stage of infection; thus, new drugs are urgently needed. Here, we describe a previously unidentified series of quinazoline compounds with potential against <i>Trypanosoma cruzi</i> and the related trypanosomatid parasites <i>Trypanosoma brucei</i> and <i>Leishmania donovani</i>. We demonstrated partial efficacy of a lead quinazoline compound in a mouse model of acute Chagas disease. Mechanism of action studies using several orthogonal approaches showed that this quinazoline compound series targeted the ATP-binding pocket of <i>T. cruzi</i> lysyl-tRNA synthetase 1 (KRS1). A high-resolution crystal structure of KRS1 bound to the drug indicated binding interactions that led to KRS1 inhibition. Our study identified KRS1 as a druggable target for treating <i>T. cruzi</i> infection in a mouse model. This quinazoline series shows potential for treating Chagas disease but will require further development to become a future treatment for this neglected disease.</div>\",\"PeriodicalId\":21580,\"journal\":{\"name\":\"Science Translational Medicine\",\"volume\":\"17 806\",\"pages\":\"\"},\"PeriodicalIF\":14.6000,\"publicationDate\":\"2025-07-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Science Translational Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.science.org/doi/10.1126/scitranslmed.adu4564\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Translational Medicine","FirstCategoryId":"3","ListUrlMain":"https://www.science.org/doi/10.1126/scitranslmed.adu4564","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Antitrypanosomal quinazolines targeting lysyl-tRNA synthetase show partial efficacy in a mouse model of acute Chagas disease
The protozoan parasite Trypanosoma cruzi causes Chagas disease, which is among the deadliest parasitic infections in Latin America. Current therapies are toxic and lack efficacy against the chronic stage of infection; thus, new drugs are urgently needed. Here, we describe a previously unidentified series of quinazoline compounds with potential against Trypanosoma cruzi and the related trypanosomatid parasites Trypanosoma brucei and Leishmania donovani. We demonstrated partial efficacy of a lead quinazoline compound in a mouse model of acute Chagas disease. Mechanism of action studies using several orthogonal approaches showed that this quinazoline compound series targeted the ATP-binding pocket of T. cruzi lysyl-tRNA synthetase 1 (KRS1). A high-resolution crystal structure of KRS1 bound to the drug indicated binding interactions that led to KRS1 inhibition. Our study identified KRS1 as a druggable target for treating T. cruzi infection in a mouse model. This quinazoline series shows potential for treating Chagas disease but will require further development to become a future treatment for this neglected disease.
期刊介绍:
Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research.
The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases.
The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine.
The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.