Investigating the pharmacology of 8-Aminoquinoline antimalarial agents.

研究 8-氨基喹啉抗疟药的药理学。

• 批准号: 2269400
• 金额: --
• 依托单位: Liverpool School of Tropical Medicine
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2269400
• 关键词: Investigating; pharmacology; Aminoquinoline; antimalarial; agents.

Despite continued efforts towards eradication, malaria remains one of the top killers of the developing world. With the rise of multidrug resistant (MDR) malarial strains, it is now a matter of urgency to eradicate malaria in the Mekong Region of Cambodia where these strains originate. Currently only one class of compounds, the 8-Aminoquinolines (8AQ) have efficacy against the liver stages and dormant hypnozoites of Plasmodium vivax (P. vivax), a prevalent species in Southeast Asia. Use of these drugs, and therefore any eradication efforts, are significantly hampered by toxicity, namely haemolytic anaemia which is especially severe in those with inborn Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency. The mode of action, toxicity and pharmacology of this class remains largely unknown. Research has begun to address these knowledge gaps; however, it is largely impeded by lack of appropriate physiologically relevant models that can accurately mimic in-vivo infection active drug metabolism. 3D human liver organoid models are proposed to bridge this gap, providing expression of key Cytochrome P450 enzymes for metabolism, and a platform for sustained parasite infection. The aim of this project is to investigate the pharmacokinetic and pharmacodynamic drivers of liver stage antimalarial activity and toxicity in 8AQ compounds. The project will depend on the development and application of physiologically relevant in-vitro models that allow for real-time assessment of activity of 8AQ compounds and their metabolites and will couple results with computational methods to conduct a comparative study of 8AQ compounds in combination with other licenced antimalarial agents, in order to unpick the pharmacological properties of the 8AQ class.

尽管继续努力消除，但疟疾仍然是发展中国家的主要杀手之一。随着多药抗性（MDR）疟疾菌株的兴起，现在要在柬埔寨湄公河地区消除这些菌株起源的疟疾是紧迫的问题。目前，只有一类化合物，8-氨基喹啉（8AQ）对肝脏阶段和疟原虫疟原虫（vivax）的肝脏阶段和休眠性催眠症具有疗效，这是东南亚普遍存在的物种。这些药物的使用，因此，任何根除的工作都受到毒性的严重阻碍，即溶血性贫血，在先天葡萄糖-6-磷酸盐脱氢酶（G6PD）缺陷的人中尤为严重。该类别的作用方式，毒性和药理学基本上仍然未知。研究已经开始解决这些知识差距。但是，由于缺乏适当的生理相关模型，可以准确地模仿体内感染活性药物代谢。提出了3D人肝脏器官模型来弥合这一间隙，为代谢提供了关键的细胞色素P450酶，并提供了持续寄生虫感染的平台。该项目的目的是研究8AQ化合物中肝阶段抗疟疾活性和毒性的药代动力学和药效动力驱动因素。该项目将取决于生理相关的体外模型的开发和应用，这些模型允许对8AQ化合物及其代谢产物的活性进行实时评估，并将将结果与计算方法相结合，以对8AQ化合物进行比较研究，并将其与其他许可的抗原抗体结合使用，以取消抗药性类别，以取消8AAQ类别的药理学性质。