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

用于疟疾治疗的 Kalihinol 支架的 Hit-to-Lead 开发

• 批准号: 10228612
• 负责人: CHOUKRI BEN MAMOUN
• 金额: $ 70.65万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-21 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228612
• 关键词: Address; Africa; Antimalarials; Artemisinins; Biological; Biological Availability; Biology; Blood; Cessation of life; Chemicals; Clinical; Combined Modality Therapy; Country; Culicidae; Data; Development; Dose; Drug Kinetics; Drug resistance; Drug usage; Erythrocytes; Family; Genomic approach; Goals; Growth; Hand; Health; Human; In Vitro; Individual; Infection; Laboratories; Lead; Learning; Life Cycle Stages; MED6 gene; Malaria; Metabolic; Metabolism; Mus; Natural Products; Parasite resistance; Parasites; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Plasmodium; Plasmodium falciparum; Plasmodium vivax; Property; Prophylactic treatment; Publications; Rattus; Recrudescences; Reporting; Research; Resistance; Route; Safety; Sampling; Sex Differentiation; Sexual Transmission; Solubility; Structure-Activity Relationship; Therapeutic Index; Translating; Treatment Cost; Vaccines; Work; analog; base; chemical synthesis; clinical candidate; combat; course development; design; drug action; drug candidate; drug-sensitive; efficacy evaluation; efficacy study; functional group; global health; improved; in vivo; inhibitor/antagonist; malaria infection; member; mortality; multidisciplinary; nanomolar; next generation; novel; novel therapeutic intervention; novel therapeutics; pre-clinical; preclinical development; prevent; programs; resistance mechanism; resistant Plasmodium falciparum; safety study; scaffold; screening; transmission process; vector

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.

项目摘要 Kalihinol支架的疟疾治疗的命中率开发 该协作研究计划的最终目标是确定抗疟疾临床候选者 Isocyanoterpenes的Kalihinol家族的类似物，这是一种有效的天然产品类别 对恶性疟原虫的活性，恶性疟原虫是人类疟疾最致命形式的致病药物。药品 阻力仍然是阻碍全球努力控制疟疾感染的全球努力的主要因素 死亡率和降低治疗成本。抵抗疟疾耐药性需要发展 以前未用于疟疾疗法的新型化学物质和新型治疗的实施 最佳使用这些化学物质以防止耐药性的策略。我们在我们的初步数据 实验室支持这项研究的前提，即可以作为新型抗疟药开发kalihinols 代理商。我们的数据表明（i）Kalihinol天然产品在血液阶段具有强大的活性 药物敏感和耐药性恶性疟原虫菌株在低纳摩尔范围内具有IC50值，（ii） 这些化合物可以适合快速而简化的合成路线，并产生保留有效的类似物 抗性活性，（iii）它们是安全的，具有高治疗指数，（iv）它们的异义函数组是 相对稳定，与代谢相对稳定，（v）它们可以通过新颖的作用方式发挥抗疟疾活性。 在这一数据主体的基础上，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，并揭示其作用方式。目标 1，我们将进一步表征铅kalihinol类似物的生物学活性和药理特性 已经掌握的，包括它们抑制药物敏感和耐药性疟疾寄生虫的生长的能力 在人类红细胞内，阻止性别分化和向蚊子传播，并消除 小鼠致死性疟疾感染。在AIM 2中，我们将采用允许的一般化学合成设计 获取许多不同的kalihinol型化合物，目的是优化效力和药理学 特性。具有出色效力，选择性和安全性概况的化合物将在体内进一步评估 功效和安全性。在AIM 3中。药物的作用方式和寄生虫的可能机制 使用最先进的细胞，代谢，化学生物学将进一步阐明对它们的耐药性 和基因组学方法。这个协作和多学科项目与人类健康有关 因为它有可能基于新型化学物质产生新的临床前抗疟疾铅 从来没有用于疟疾疗法。