Hit-to-Lead Development of the Kalihinol Scaffold for Malaria Treatment

项目概要 用于疟疾治疗的 Kalihinol 支架的 Hit-to-Lead 开发 该合作研究计划的最终目标是确定抗疟临床候选药物 异氰萜烯醇家族的类似物，是一类正在研究中的天然产物，具有有效的功效 对恶性疟原虫具有活性，恶性疟原虫是人类最致命的疟疾的病原体。药物 耐药性仍然是阻碍全球控制疟疾感染努力的主要因素，降低了疟疾感染率 死亡率并降低治疗费用。对抗疟疾耐药性需要开发 以前未用于疟疾治疗的新型化学物质，以及新治疗方法的实施 最佳使用这些化学物质以防止耐药性的策略。我们生成的初步数据 实验室支持这项研究的前提，即 kalihinols 可以开发为新型抗疟药 代理。我们的数据表明 (i) kalihinol 天然产物对血液阶段具有有效的活性 IC50 值在低纳摩尔范围内的药物敏感型和耐药型恶性疟原虫菌株，(ii) 这些化合物适合快速和简化的合成路线，产生保留有效活性的类似物 抗疟活性，(iii) 它们是安全的，具有高治疗指数，(iv) 它们的异腈官能团是 代谢相对稳定，并且（v）它们可以通过一种新的作用模式发挥其抗疟活性。 基于这些数据，我们建议深入研究这些数据的结构-活动关系 化合物，表征其体外和体内功效和安全性，并揭示其作用模式。瞄准 1、我们将进一步表征铅kalihinol类似物的生物活性和药理特性 已经掌握的技术，包括抑制药物敏感和耐药疟原虫生长的能力 在人类红细胞内，阻止性别分化和传播给蚊子，并消除 小鼠致命的疟疾感染。在目标 2 中，我们将采用通用化学合成设计，允许 获得许多不同的 kalihinol 型化合物，目的是优化效力和药理学 属性。具有优异效力、选择性和安全性的化合物将在体内进一步评估 功效和安全性。在目标 3 中，药物的作用方式和寄生虫的可能机制 将使用最先进的细胞、代谢、化学生物学进一步阐明对它们的抵抗力 和基因组学方法。这个协作和多学科项目与人类健康相关 因为它有可能基于一类新型化学物质产生新的临床前抗疟药物 以前从未用于疟疾治疗。

Project Summary Hit-to-Lead Development of the Kalihinol Scaffold for Malaria Treatment The ultimate goal of this collaborative research program is to identify antimalarial clinical candidates among analogues of the kalihinol family of isocyanoterpenes, an understudied class of natural products with potent activity against Plasmodium falciparum, the causative agent of the deadliest form of human malaria. Drug resistance remains the leading factor hampering global efforts aimed at controlling malaria infection, lowering mortality rates and reducing the cost of treatment. Countering malaria drug resistance requires development of novel classes of chemicals not previously used in malaria therapy, and implementation of novel therapeutic strategies for optimal use of these chemicals to prevent drug resistance. Preliminary data generated in our laboratories support the premise of this research that the kalihinols could be developed as novel antimalarial agents. Our data demonstrate that (i) kalihinol natural products have potent activity against blood stages of both drug-sensitive and drug-resistant P. falciparum strains with IC50 values in the low nanomolar range, (ii) these compounds are amenable to rapid and simplified synthesis routes producing analogues that retain potent antimalarial activity, (iii) they are safe, with high therapeutic indices, (iv) their isonitrile functional groups are relatively stable to metabolism, and (v) they may exert their antimalarial activity through a novel mode of action. Building upon this body of data, we propose to delve deeply into the structure-activity relationship of these compounds, characterize their in vitro and in vivo efficacy and safety, and unravel their mode of action. In Aim 1, we will further characterize the biological activity and pharmacological properties of lead kalihinol analogues already in hand, including their ability to inhibit growth of drug-sensitive and drug-resistant malaria parasites within human red blood cells, to block sexual differentiation and transmission to mosquitoes, and to eliminate lethal malaria infection in mice. In Aim 2, we will embrace a general chemical synthesis design that permits access to many diverse kalihinol-type compounds, with the goal of optimizing potency and pharmacological properties. Compounds with excellent potency, selectivity and safety profiles will be further evaluated in vivo for efficacy and safety. In Aim 3. both the mode of action of the drugs and the parasite's possible mechanisms of resistance against them will be further elucidated using state-of-the-art cellular, metabolic, chemical biology and genomics approaches. This collaborative and multidisciplinary project is of relevance to human health because of its potential to produce new preclinical antimalarial leads based on a novel class of chemicals never before used in malaria therapy.