Investigating the pharmacology of 8-Aminoquinoline antimalarial agents.

尽管为消灭疟疾作出了持续努力，但疟疾仍然是发展中世界的头号杀手之一。随着多药耐药（MDR）疟疾菌株的增加，现在迫切需要在这些菌株起源的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）对间日疟原虫（P. vivax）的肝期和休眠催眠子有效，间日疟原虫是东南亚的流行物种。这些药物的使用以及因此任何根除努力都受到毒性的严重阻碍，即溶血性贫血，这在先天性葡萄糖-6-磷酸脱氢酶（G6 PD）缺乏症患者中尤其严重。这类药物的作用方式、毒性和药理学仍基本未知。研究已经开始解决这些知识差距;然而，它在很大程度上受到缺乏适当的生理相关模型，可以准确地模拟体内感染活性药物代谢的阻碍。提出了3D人类肝脏类器官模型来弥合这一差距，为代谢提供关键细胞色素P450酶的表达，并为持续的寄生虫感染提供平台。本项目的目的是研究8AQ化合物中肝脏阶段抗疟活性和毒性的药代动力学和药效学驱动因素。该项目将依赖于生理相关的体外模型的开发和应用，这些模型允许实时评估8AQ化合物及其代谢物的活性，并将结果与计算方法相结合，以进行8AQ化合物与其他许可的抗疟药的比较研究，以解开8AQ类的药理学特性。

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.