Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia.
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia.
Int J Parasitol Drugs Drug Resist. 2022 Dec;20:135-144. doi: 10.1016/j.ijpddr.2022.11.001. Epub 2022 Nov 11.
New antimalarial compounds with novel mechanisms of action are urgently needed to combat the recent rise in antimalarial drug resistance. Phenotypic high-throughput screens have proven to be a successful method for identifying new compounds, however, do not provide mechanistic information about the molecular target(s) responsible for antimalarial action. Current and emerging target identification methods such as in vitro resistance generation, metabolomics screening, chemoproteomic approaches and biophysical assays measuring protein stability across the whole proteome have successfully identified novel drug targets. This review provides an overview of these techniques, comparing their strengths and weaknesses and how they can be utilised for antimalarial target identification.
新的抗疟化合物具有新颖的作用机制,对于对抗最近抗疟药物耐药性的上升至关重要。表型高通量筛选已被证明是识别新化合物的成功方法,但不能提供负责抗疟作用的分子靶标(s)的机制信息。当前和新兴的靶标识别方法,如体外耐药性产生、代谢组学筛选、化学蛋白质组学方法以及测量整个蛋白质组中蛋白质稳定性的生物物理测定,已成功鉴定出新的药物靶标。本文综述了这些技术,比较了它们的优缺点,以及如何将它们用于抗疟靶标识别。