Discovery of 4-aminoquinoline therapeutics for visceral leishmaniasis

发现内脏利什曼病的 4-氨基喹啉疗法

• 批准号: 8207443
• 负责人: Peter C. Melby
• 金额: $ 49.98万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2012-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8207443
• 关键词: Discovery; aminoquinoline; therapeutics; visceral; leishmaniasis

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15-AI-103: Develop drugs for neglected tropical diseases, with a special emphasis on malaria. New drugs are desperately needed to treat visceral leishmaniasis (VL), a tropical disease cause by the protozoan Leishmania donovani. This proposal is focused on the discovery of new compounds that will feed into the pipeline bringing new therapeutics to patients with VL. The Specific Aim of this proposal is to identify novel drug candidates for visceral leishmaniasis through optimization of 4-aminoquinoline lead compounds. A novel ex vivo splenic explant model, derived from hamsters infected with L. donovani, will be used to identify new 4-aminoquinoline derivatives with anti-leishmanial activity. This new model, which was recently developed in our lab, capitalizes on the pathogenic similarities between hamster and human VL and offers the unique opportunity to discover compounds that are active against the parasite within the context of the pathogenic mechanisms that contribute to progressive disease. We propose to identify candidate drugs for the treatment of VL by chemical optimization of the 4-aminoquinoline lead compounds we previously identified. We will do this through a systematic, parallel, and iterative process of repeated cycles of synthesis of small (40- 80 compound) iterative libraries of 4-aminoquinoline derivatives, screening of the libraries for anti-leishmanial activity, toxicity, and drug-likeness, and repeated SAR analysis to generate new compounds for testing. Quinoline molecules have several notable characteristics that favor drug development and the availability of extensive data related to structure-activity relationship (SAR) and the prior successful development of quinolines for malaria will greatly facilitate the proposed studies. The proposed approach is feasible because of the rapidity with which new compounds will be synthesized and tested. The in vitro assays to be used for compound toxicity and absorption and stability/metabolism are standard for the field. The ex vivo splenic explant model is an innovative approach because the anti-leishmanial activity of 4-aminoquinoline derivatives will be tested (1) in a medium- to high-throughput format, (2) within the cellular microenvironment of the spleen, which includes the cells that exert immunopathologic effects known to profoundly influence parasite replication or killing, (3) against intracellular amastigotes (mammalian stage) rather than axenically cultured promastigotes (vector stage), which show discordant responses to antileishmanial compounds, (4) against amastigotes in splenic macrophages, which are functionally distinct from the traditionally used peritoneal macrophages, and (5) will be identified as having anti-leishmanial activity whether it is through direct parasite killing and/or indirect immune-mediated mechanisms. Furthermore, the integration of the chemical optimization and SAR analysis by Dr. Frantz's laboratory with the biological testing by Dr. Melby's laboratory will enable the efficient discovery of new compounds suitable for future in vivo efficacy testing in the pre-clinical hamster model of progressive VL. PUBLIC HEALTH RELEVANCE: Visceral leishmaniasis (VL) is a major public health problem with millions of cases worldwide. This proposal is focused on the discovery of new compounds that will feed into the pipeline bringing new therapeutics to patients with VL.

描述（由申请人提供）：本申请应解决广泛的挑战领域（15）转化科学和特定挑战主题，15-AI-103：开发用于被忽视的热带疾病的药物，并特别强调疟疾。迫切需要新药来治疗内脏利什曼病（VL），这是原生动物利什曼原虫Donovani引起的一种热带疾病。该提案的重点是发现新化合物，这些化合物将带入管道中，从而为VL患者带来新的治疗剂。该提案的具体目的是通过优化4-氨基喹啉铅化合物来鉴定内脏利什曼病的新型药物。一种新型的体内脾外植体模型，该模型源自感染了多诺瓦氏乳杆菌的仓鼠，将用于鉴定具有抗leish人类活性的新的4-氨基喹啉衍生物。该新模型最近在我们的实验室中开发，它利用了仓鼠和人VL之间的致病性相似性，并提供了独特的机会，可以发现在有助于渐进疾病的致病机制的背景下发现对寄生虫有效的化合物。我们建议通过化学优化我们先前鉴定的4-氨基喹啉铅化合物来鉴定候选药物来治疗VL。我们将通过重复的4-氨基喹啉衍生物的小（40-80-80-复合）迭代库的合成的重复循环的系统，平行和迭代的过程来做到这一点。喹啉分子具有几个值得注意的特征，有利于药物开发和与结构活性关系（SAR）相关的广泛数据的可用性，并且先前成功开发了喹啉疟疾的喹啉，这将极大地促进拟议的研究。提出的方法是可行的，因为对新化合物进行了合成和测试的速度。用于复合毒性和吸收和稳定性/代谢的体外测定是该领域的标准。离体脾eppy依模型是一种创新的方法疗程（哺乳动物阶段）而不是轴承培养的前寄生植物（矢量阶段），这些反应对抗精神经会化合物的反应不一致，（4）针对脾巨噬细胞中的amastigotes，它们在功能上与传统上使用的腹膜巨噬细胞和（5）在功能上不同，并且在脉络下是否会杀死抗疾病的活动，这是否会杀死抗疾病的活动。免疫介导的机制。此外，弗朗兹博士的实验室与梅尔比博士实验室的生物测试的化学优化和SAR分析的整合将使在临时型号的渐进型仓鼠模型中有效地发现适合未来体内疗效未来的新化合物。 公共卫生相关性：内脏利什曼病（VL）是全球数百万个病例的主要公共卫生问题。该提案的重点是发现新化合物，这些化合物将带入管道中，从而为VL患者带来新的治疗剂。