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) 转化科学和具体挑战主题 15-AI-103：开发治疗被忽视的热带疾病的药物，特别强调疟疾。迫切需要新药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化合物，这些化合物将进入管道，为 VL 患者带来新的治疗方法。该提案的具体目标是通过优化 4-氨基喹啉先导化合物来确定治疗内脏利什曼病的新候选药物。一种新型离体脾外植体模型，源自感染杜氏利什曼原虫的仓鼠，​​将用于鉴定具有抗利什曼原虫活性的新型 4-氨基喹啉衍生物。我们实验室最近开发的这个新模型利用了仓鼠和人类 VL 之间的致病相似性，并提供了独特的机会来发现在导致疾病进展的致病机制背景下对寄生虫具有活性的化合物。我们建议通过对我们之前确定的 4-氨基喹啉先导化合物进行化学优化来确定治疗 VL 的候选药物。我们将通过系统、并行和迭代的过程来实现这一点，该过程重复循环合成 4-氨基喹啉衍生物的小型（40-80 种化合物）迭代文库，筛选文库的抗利什曼原虫活性、毒性和药物相似性，并重复 SAR 分析以生成新的化合物进行测试。喹啉分子具有一些有利于药物开发的显着特征，并且与构效关系（SAR）相关的大量数据的可用性以及先前成功开发的用于疟疾的喹啉将极大地促进拟议的研究。由于新化合物的合成和测试速度很快，所提出的方法是可行的。用于化合物毒性和吸收以及稳定性/代谢的体外测定是该领域的标准。离体脾外植体模型是一种创新方法，因为 4-氨基喹啉衍生物的抗利什曼原虫活性将在 (1) 以中高通量形式进行测试，(2) 在脾细胞微环境中进行测试，其中包括已知发挥免疫病理作用的细胞可深刻影响寄生虫的复制或杀伤，（3）针对细胞内无鞭毛体（哺乳动物阶段）而不是无菌培养的前鞭毛体（载体）阶段），显示出对抗利什曼原虫化合物的不一致反应，（4）针对脾巨噬细胞中的无鞭毛体，其功能与传统使用的腹膜巨噬细胞不同，以及（5）无论是通过直接寄生虫，都将被鉴定为具有抗利什曼原虫活性杀伤和/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 博士实验室的生物测试相结合，将能够有效地发现适合未来在进行性 VL 临床前仓鼠模型中进行体内功效测试的新化合物。 。 公共卫生相关性：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化合物，这些化合物将进入管道，为 VL 患者带来新的治疗方法。