Investigating the pharmacology of 8-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.