Investigating the pharmacology of 8-Aminoquinoline antimalarial agents.

尽管继续努力根除疟疾，但疟疾仍然是发展中国家的头号杀手之一。随着耐多药疟疾菌株的增加，现在迫切需要在这些菌株的发源地柬埔寨湄公河地区根除疟疾。目前只有一类化合物8-氨基喹啉（8AQ）对东南亚流行的间日疟原虫（P. vivax）的肝期和休眠催眠虫有效。这些药物的使用，因此任何根除努力，都受到毒性的严重阻碍，即溶血性贫血，这在先天葡萄糖-6-磷酸脱氢酶（G6PD）缺乏症患者中尤其严重。这类药物的作用方式、毒性和药理学在很大程度上仍然未知。研究已经开始解决这些知识差距；然而，由于缺乏适当的生理相关模型来准确模拟体内感染和活性药物代谢，这在很大程度上受到阻碍。3D人类肝脏类器官模型的提出弥补了这一差距，提供了关键细胞色素P450酶的代谢表达，以及持续寄生虫感染的平台。本项目的目的是研究8AQ化合物的肝期抗疟活性和毒性的药动学和药效学驱动因素。该项目将依赖于与生理相关的体外模型的开发和应用，该模型允许实时评估8AQ化合物及其代谢物的活性，并将结果与计算方法相结合，对8AQ化合物与其他已获许可的抗疟疾药物联合进行比较研究，以揭示8AQ类药物的药理学特性。

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.