Development of Novel Therapeutics for Leishmaniasis

项目总结 关联性。据估计，利什曼原虫感染了1200万人，目前还没有令人满意的治疗方法 但仍可用。这项提议将推进从表型筛选中出现的3个支架 开发新型有效的口服生物可用药物治疗利什曼病。总结。一个 先前对利什曼原虫致病细胞内无鞭毛体阶段的表型筛选 已经确定了3种对无鞭毛虫有效的化学支架。每一种命中化合物都展示了 纳米分子对生长在组织培养巨噬细胞中的无鞭毛体的抑制作用及其理化效应 具有开发一种新型口服生物利用药物的前景的特性。每个脚手架的相似之处 准备好并在体外测试对无鞭毛虫的效力，最佳 Absorption/distribution/metabolism/excretion/toxicity(ADMET)图谱，可接受的体内药代动力学 (PK)，以及在内脏利什曼病小鼠模型中控制疾病的有效性。成立后 在最初的结构-活性关系中，将进行广泛的药物化学计划，以 开发具有最佳综合性能的口服生物利用药的类似物，并改进任何潜在的 原版大热中出现的不足之处。不同支架对多种利什曼原虫的杀灭效果 对抗药性的田间分离株将在早期阶段进行测试，以确定每种 脚手架，适用于对抗引起不同类型利什曼病的各种寄生虫，或 对目前使用的其他抗利什曼病药物没有预先确定的耐药性，尽管不是最优的。这个 将监测抗药性的发展速度，以确保所追查的线索是合理的 在野外使用时，能稳定地抵抗抗性的出现。与广泛的医学研究相关联 化学程序、体内药代动力学和急性毒性研究以及控制内脏感染的能力 在老鼠和仓鼠中，将确定达到顶端的合成导联源于最初的3次命中。 总体目标是开发几个具有极具前景的特征的线索，以实现最终的发展 迫切需要新的有效药物来对抗这种广泛存在且控制不善的寄生虫 疾病。

PROJECT SUMMARY Relevance. Leishmania parasites infect an estimated 12 million individuals, and no satisfactory treatments are yet available. This proposal will advance 3 scaffolds that have emerged from a phenotypic screen for development of leads towards novel effective orally-bioavailable drugs against leishmaniasis. Summary. A previous phenotypic screen against the disease-causing intracellular amastigote stage of Leishmania parasites has identified 3 chemical scaffolds with potent efficacy against amastigotes. Each hit compound exhibits nanomolar efficacy against amastigotes growing in tissue culture macrophages and has physical and chemical properties suggesting promise for development of a novel orally bioavailable drug. Analogs of each scaffold will be prepared and tested for efficacy against amastigotes in vitro, optimal absorption/distribution/metabolism/excretion/toxicity (ADMET) profiles, acceptable in vivo pharmacokinetics (PK), and efficacy in controlling disease in a murine model of visceral leishmaniasis. Following establishment of initial structure-activity relationships, an extensive medicinal chemistry program will be undertaken to develop analogs with the best overall properties for orally bioavailable drugs and to improve upon any potential deficits that emerge in the original hits. The efficacy of each scaffold against multiple species of Leishmania and against drug resistant field isolates will be tested at an early stage to ascertain the potential of each scaffold for applicability against a broad range of parasites causing distinct types of leishmaniasis and with or without pre-established resistance to other currently employed, albeit non-optimal, antileishmanial drugs. The rate of development of resistance will be monitored to ensure that leads that are pursued will be reasonably stable against emergence of resistance during use in the field. In association with an extensive medicinal chemistry program, in vivo pharmacokinetics and acute toxicity studies and ability to control visceral infections in mice and hamsters will be determined to arrive at the top synthetic leads originating from the original 3 hits. The overall objective is to develop several leads with highly promising characteristics for ultimate development of desperately needed novel and effective drugs against this widespread and poorly controlled parasitic disease.