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

项目摘要 用于疟疾治疗的Kalihinol支架的命中-铅开发 这项合作研究计划的最终目标是在以下人群中确定抗疟临床候选药物： 异氰萜类的kalihinol家族的类似物，一种未充分研究的具有有效的 抗恶性疟原虫的活性，恶性疟原虫是最致命的人类疟疾的病原体。药物 耐药性仍然是阻碍全球控制疟疾感染的主要因素， 降低死亡率，降低治疗费用。消除疟疾抗药性需要发展 以前未用于疟疾治疗的新型化学品，以及新型治疗药物的应用 最佳使用这些化学品的策略，以防止耐药性。在我们的实验室中生成的初步数据 实验室支持这项研究的前提，即kalihinols可以开发为新的抗疟疾药物。 剂.我们的数据表明：（i）kalihinol天然产物具有有效的活性， 具有低纳摩尔范围内的IC 50值的药物敏感性和耐药性恶性疟原虫菌株，（ii） 这些化合物适合于快速和简化的合成路线， 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 对代谢相对稳定，和（v）它们可以通过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化合物的结构-活性关系。 化合物，表征它们的体外和体内功效和安全性，并阐明它们的作用模式。在Aim中 1，我们将进一步表征铅kalihinol类似物的生物活性和药理性质 包括抑制对药物敏感和耐药的疟疾寄生虫生长的能力 在人体红细胞内，阻止性分化和传播给蚊子，并消除 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， 获得许多不同的kalihinol型化合物，以优化效力和药理学的目标， 特性.具有优异效力、选择性和安全性特征的化合物将在体内进一步评价， 有效性和安全性。目标3.药物的作用方式和寄生虫的可能机制， 利用最先进的细胞、代谢、化学生物学， 和基因组学方法。这一合作和多学科项目与人类健康有关 因为它有可能基于一类新的化学物质产生新的临床前抗疟药物 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.