Department of Molecular Genetics and Microbiology, Duke University Medical Center, 213 Research Drive, Durham, NC 27710, USA.
Department of Chemistry, Duke University, 124 Science Drive, Durham, NC 27708, USA.
Chembiochem. 2021 Aug 17;22(16):2591-2599. doi: 10.1002/cbic.202100155. Epub 2021 Jun 10.
Emerging Plasmodium parasite drug resistance is threatening progress towards malaria control and elimination. While recent efforts in cell-based, high-throughput drug screening have produced first-in-class drugs with promising activities against different Plasmodium life cycle stages, most of these antimalarial agents have elusive mechanisms of action. Though challenging to address, target identification can provide valuable information to facilitate lead optimization and preclinical drug prioritization. Recently, proteome-wide methods for direct assessment of drug-protein interactions have emerged as powerful tools in a number of systems, including Plasmodium. In this review, we will discuss current chemoproteomic strategies that have been adapted to antimalarial drug target discovery, including affinity- and activity-based protein profiling and the energetics-based techniques thermal proteome profiling and stability of proteins from rates of oxidation. The successful application of chemoproteomics to the Plasmodium blood stage highlights the potential of these methods to link inhibitors to their molecular targets in more elusive Plasmodium life stages and intracellular pathogens in the future.
新兴疟原虫寄生虫药物耐药性正在威胁疟疾控制和消除工作的进展。虽然最近在基于细胞的高通量药物筛选方面的努力已经产生了具有针对不同疟原虫生命周期阶段的有前途的活性的一类首创药物，但这些抗疟药物中的大多数都具有难以捉摸的作用机制。尽管难以解决，但靶标鉴定可以提供有价值的信息，以促进先导化合物优化和临床前药物优先级排序。最近，用于直接评估药物-蛋白质相互作用的蛋白质组学方法已成为包括疟原虫在内的许多系统中的强大工具。在这篇综述中，我们将讨论已被改编用于抗疟药物靶标发现的当前化学蛋白质组学策略，包括基于亲和力和基于活性的蛋白质分析以及基于能量的技术热蛋白质组分析和氧化速率的蛋白质稳定性。化学蛋白质组学在疟原虫血阶段的成功应用突显了这些方法在未来将抑制剂与更难以捉摸的疟原虫生命阶段和细胞内病原体的分子靶标联系起来的潜力。
