The evolution of PfCRT from a carrier with a natural function to a drug transporting system in Plasmodium falciparum

PfCRT从具有天然功能的载体到恶性疟原虫药物转运系统的演变

• 批准号: 258470567
• 负责人: Professor Dr. Michael Lanzer
• 金额: --
• 依托单位: Abteilung Parasitologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/258470567?language=en
• 关键词: evolution; PfCRT; carrier; natural; function

Drug resistance remains a pending problem in the control of malaria. Of particular concern is the reduced responsiveness of the human malaria parasite Plasmodium falciparum to quinolone antimalarial drugs. Quinoline derivatives have been used in malaria chemotherapy for more than a century. They are still indispensable, serving as partner drugs to artemisinin derivatives, which as artemisinin combination therapy comprise the current mainstay of malaria chemotherapy. A gene frequently contributing to response variations to quinolines, but also to a large number of structurally unrelated bioactive compounds, is pfcrt encoding a drug/metabolite carrier system. The objective of this project is i) to identify the natural substrate(s) of PfCRT; ii) to study how PfCRT has evolved from a metabolite carrier to a drug transporting system; iii) to develop tools to predict how PfCRT will mutate in the future when exposed to new drug challenges; and iv) to explore whether PfCRT can acquire a multi-drug resistance capability. The project brings together two groups with complementary expertise: a parasitology laboratory with a track record in drug resistance and an electrophysiology laboratory with a track record in the functional characterization of ion and metabolite transport systems. Both groups have successfully worked together. The project involves selection of PfCRT variants that confer response variations to diverse drugs in P. falciparum, the functional expression of PfCRT variants in Xenopus laevis oocytes, the investigation of the substrate specificity of PfCRT-mediated currents, the role of PfCRT in iron transport, transport studies using radioactive tracers, and live cell imaging. In depth knowledge about the structure and function of PfCRT will be crucial to efforts to maintain the clinical efficacy of quinoline antimalarial drugs and to develop effective strategies aimed at inhibiting the transport functions of PfCRT.

抗药性仍然是控制疟疾的一个悬而未决的问题。特别令人关切的是，人类疟疾寄生虫恶性疟原虫对喹诺酮类抗疟药物的反应性降低。喹啉衍生物已用于疟疾化疗超过世纪。它们仍然是不可或缺的，是青蒿素衍生物的伙伴药物，而青蒿素衍生物作为青蒿素综合疗法是目前疟疾化疗的主要手段。一个基因，经常有助于响应变化的喹啉，但也有大量的结构无关的生物活性化合物，是pfcrt编码的药物/代谢物载体系统。本项目的目的是：i）鉴定PfCRT的天然底物; ii）研究PfCRT如何从代谢物载体演变为药物转运系统; iii）开发预测PfCRT在未来暴露于新药挑战时如何突变的工具;以及iv）探索PfCRT是否可以获得多药耐药能力。该项目汇集了两个具有互补专长的小组：一个是具有抗药性跟踪记录的寄生虫学实验室，另一个是具有离子和代谢物运输系统功能特性跟踪记录的电生理学实验室。这两个团体成功地合作了。该项目包括选择PfCRT变体，赋予恶性疟原虫中不同药物的反应变化，PfCRT变体在非洲爪蟾卵母细胞中的功能表达，PfCRT介导电流的底物特异性的研究，PfCRT在铁转运中的作用，使用放射性示踪剂的转运研究和活细胞成像。深入了解PfCRT的结构和功能，将是至关重要的努力，以保持喹啉抗疟药物的临床疗效，并制定有效的策略，旨在抑制PfCRT的运输功能。