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.

尽管我们不断努力根除疟疾，但疟疾仍然是发展中国家的头号杀手之一。随着耐多药（MDR）疟疾菌株的增加，在这些菌株的发源地柬埔寨湄公河地区根除疟疾已成为当务之急。目前只有一类化合物，即 8-氨基喹啉 (8AQ)，对东南亚流行的间日疟原虫 (P. vivax) 的肝脏阶段和休眠子孢子有效。这些药物的使用以及任何根除努力都受到毒性的严重阻碍，即溶血性贫血，这对于先天性 6-磷酸葡萄糖脱氢酶 (G6PD) 缺乏症的患者尤其严重。此类药物的作用方式、毒性和药理学仍然很大程度上未知。研究已经开始解决这些知识差距；然而，由于缺乏能够准确模拟体内感染活性药物代谢的适当的生理相关模型，这在很大程度上受到阻碍。 3D 人类肝脏类器官模型旨在弥补这一差距，提供代谢关键细胞色素 P450 酶的表达，并为持续寄生虫感染提供平台。该项目的目的是研究 8AQ 化合物肝期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体外模型的开发和应用，这些模型可以实时评估 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 化合物与其他获得许可的抗疟药物组合进行比较研究，以揭示 8AQ 类药物的药理学特性。