Antitrypanosomal quinazolines targeting lysyl-tRNA synthetase show partial efficacy in a mouse model of acute Chagas disease

IF 14.6 1区医学 Q1 CELL BIOLOGY

Science Translational Medicine Pub Date : 2025-07-09 DOI:10.1126/scitranslmed.adu4564

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

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引用次数: 0

Abstract

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.

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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

原生动物寄生虫克氏锥虫引起恰加斯病，这是拉丁美洲最致命的寄生虫感染之一。目前的治疗方法是有毒的，对慢性感染缺乏疗效；因此，迫切需要新的药物。在这里，我们描述了一系列以前未被识别的喹唑啉化合物，它们具有抗克氏锥虫及其相关的锥虫寄生虫布鲁氏锥虫和多诺瓦利什曼原虫的潜力。我们证明了一种喹唑啉铅化合物在急性恰加斯病小鼠模型中的部分功效。通过正交试验研究表明，该喹唑啉类化合物系列靶向克氏T. crozi赖氨酸- trna合成酶1 （KRS1）的atp结合袋。与药物结合的KRS1的高分辨率晶体结构表明结合相互作用导致KRS1抑制。我们的研究在小鼠模型中发现KRS1是治疗克氏锥虫感染的可药物靶点。这种喹唑啉系列显示出治疗恰加斯病的潜力，但需要进一步开发才能成为这种被忽视疾病的未来治疗方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL

CiteScore

26.70

自引率

1.20%

发文量

309

审稿时长

1.7 months

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.