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）：本申请涉及广泛的挑战领域（15）转化科学和特定的挑战主题，15-AI-103：开发被忽视的热带疾病的药物，特别强调疟疾。迫切需要新的药物来治疗内脏利什曼病（VL），这是一种由原生动物杜氏利什曼原虫引起的热带疾病。该提案的重点是发现新的化合物，这些化合物将进入为VL患者带来新疗法的管道。该提案的具体目的是通过优化4-氨基喹啉先导化合物来鉴定用于内脏利什曼病的新型候选药物。一种新的离体脾移植模型，来自感染L。Donovani将用于鉴定具有抗利什曼原虫活性的新的4-氨基喹啉衍生物。我们实验室最近开发的这种新模型利用了仓鼠和人VL之间的致病相似性，并提供了独特的机会，在导致疾病进展的致病机制的背景下发现对寄生虫有活性的化合物。我们建议通过化学优化我们先前确定的4-氨基喹啉先导化合物来确定治疗VL的候选药物。我们将通过一个系统的、平行的和迭代的过程来实现这一点，该过程包括重复合成4-氨基喹啉衍生物的小（40- 80种化合物）迭代文库的循环，筛选文库的抗利什曼原虫活性、毒性和药物相似性，以及重复SAR分析以产生用于测试的新化合物。喹啉分子具有几个显著的特征，有利于药物开发，并且与结构-活性关系（SAR）相关的广泛数据的可用性和先前成功开发的用于疟疾的喹啉将极大地促进所提出的研究。所提出的方法是可行的，因为新的化合物将被合成和测试的速度。用于化合物毒性和吸收以及稳定性/代谢的体外试验是该领域的标准。离体脾外植体模型是一种创新的方法，因为4-氨基喹啉衍生物的抗利什曼原虫活性将（1）以中等至高通量的形式，（2）在脾的细胞微环境中进行测试，所述脾的细胞微环境包括发挥已知深刻影响寄生虫复制或杀死的免疫病理学作用的细胞，（3）抗细胞内无鞭毛体（哺乳动物阶段）而不是无菌培养的前鞭毛体（载体阶段），其显示对抗利什曼原虫化合物的不一致反应，（4）对抗脾巨噬细胞中的无鞭毛体，其在功能上不同于传统使用的腹膜巨噬细胞，和（5）将被鉴定为具有抗利什曼原虫活性，无论其是通过直接杀寄生虫和/或间接免疫介导的机制。此外，Frantz博士实验室的化学优化和SAR分析与Melby博士实验室的生物学试验相结合，将能够有效发现适用于未来进行性VL临床前仓鼠模型体内疗效试验的新化合物。 内脏利什曼病（VL）是一个主要的公共卫生问题，全世界有数百万病例。该提案的重点是发现新的化合物，这些化合物将进入为VL患者带来新疗法的管道。