The Walter and Eliza Hall Institute of Medical Research , Parkville , Victoria 3052 , Australia.
Department of Medical Biology , The University of Melbourne , Parkville , Victoria 3052 , Australia.
J Med Chem. 2019 Dec 12;62(23):10526-10562. doi: 10.1021/acs.jmedchem.9b00761. Epub 2019 Aug 20.
Malaria is a devastating disease caused by parasites, resulting in approximately 435000 deaths in 2018. The impact of malaria is compounded by the emergence of widespread resistance to current antimalarial therapies. Recently, a new strategy was initiated to screen small molecule collections against the parasite enabling the identification of new antimalarial chemotypes with novel modes of action. This initiative ushered in the modern era of antimalarial drug development, and as a result, numerous lead candidates are advancing toward or are currently in human clinical trials. In this Perspective, we describe the development pathway of four of the most clinically advanced modern antimalarials, KAE609, KAF156, DSM265, and MMV048. Additionally, the mechanism of action and life-cycle stage specificity of the four antimalarials is discussed in relation to aligning with global strategies to treat and eliminate malaria. This perspective serves as a guide to the expectations of modern antimalarial drug development.
疟疾是一种由寄生虫引起的毁灭性疾病，2018 年导致约 435000 人死亡。由于目前抗疟疗法的广泛耐药性，疟疾的影响更加严重。最近，人们启动了一项新的策略，即用小分子化合物对寄生虫进行筛选，从而鉴定出具有新型作用模式的新型抗疟化学型。这一举措开创了抗疟药物开发的现代时代，因此，许多先导候选药物正在或已经进入人体临床试验。在本观点中，我们描述了四种最具临床进展的现代抗疟药物（KAE609、KAF156、DSM265 和 MMV048）的开发途径。此外，还讨论了这四种抗疟药物的作用机制和生命周期阶段特异性，以与全球治疗和消除疟疾的策略保持一致。本观点旨在为现代抗疟药物开发的预期提供指导。
