Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, North Carolina 27708, United States.
Department of Chemistry, Duke University, Durham, North Carolina 27708, United States.
Biochemistry. 2020 Mar 3;59(8):911-920. doi: 10.1021/acs.biochem.9b01105. Epub 2020 Feb 24.
There is a pressing need for compounds with broad-spectrum activity against malaria parasites at various life cycle stages to achieve malaria elimination. However, this goal cannot be accomplished without targeting the tenacious dormant liver-stage hypnozoite that causes multiple relapses after the first episode of illness. In the search for the magic bullet to radically cure malaria, tafenoquine outperformed other candidate drugs and was approved by the U.S. Food and Drug Administration in 2018. Tafenoquine is an 8-aminoquinoline that inhibits multiple life stages of various species. Additionally, its much longer half-life allows for single-dose treatment, which will improve the compliance rate. Despite its approval and the long-time use of other 8-aminoquinolines, the mechanisms behind tafenoquine's activity and adverse effects are still largely unknown. In this Perspective, we discuss the plausible underlying mechanisms of tafenoquine's antiparasitic activity and highlight its role as a cellular stressor. We also discuss potential drug combinations and the development of next-generation 8-aminoquinolines to further improve the therapeutic index of tafenoquine for malaria treatment and prevention.
目前迫切需要广谱抗疟化合物来针对各种生命周期阶段的疟原虫，以实现消除疟疾的目标。然而，如果不针对导致首次发病后多次复发的顽强休眠肝期休眠疟原虫，这一目标就无法实现。在寻找根治疟疾的“神奇子弹”的过程中，tafenoquine 优于其他候选药物，并于 2018 年获得美国食品和药物管理局批准。tafenoquine 是一种 8-氨基喹啉，可抑制多种物种的多个生命阶段。此外，其更长的半衰期允许单剂量治疗，这将提高遵医嘱治疗的比例。尽管已经获得批准，且其他 8-氨基喹啉已长期使用，但 tafenoquine 的作用机制及其不良反应的机制在很大程度上仍不清楚。在本观点中，我们讨论了 tafenoquine 抗寄生虫活性的可能潜在机制，并强调了它作为细胞应激源的作用。我们还讨论了潜在的药物组合和下一代 8-氨基喹啉的开发，以进一步提高 tafenoquine 治疗和预防疟疾的治疗指数。
