Center for Biopharmaceuticals &, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
Angew Chem Int Ed Engl. 2019 Jan 21;58(4):957-966. doi: 10.1002/anie.201806037. Epub 2018 Oct 26.
Selective covalent modification of a targeted protein is a powerful tool in chemical biology and drug discovery, with applications ranging from identification and characterization of proteins and their functions to the development of targeted covalent inhibitors. Most covalent ligands contain an affinity motif and an electrophilic warhead that reacts with a nucleophilic residue of the targeted protein. Because the electrophilic warhead is prone to react and modify off-target nucleophiles, its reactivity should be balanced carefully to maximize target selectivity. Arylfluorosulfates have recently emerged as latent electrophiles for selective labeling of context-specific tyrosine and lysine residues in protein pockets. Here, we review the recent but intense introduction of arylfluorosulfates into the arsenal of available warheads for selective covalent modification of proteins. We highlight the untapped potential of this functional group for use in chemical biology and drug discovery.
选择性共价修饰靶蛋白是化学生物学和药物发现中的有力工具，其应用范围从蛋白质及其功能的鉴定和表征到靶向共价抑制剂的开发。大多数共价配体含有亲和基序和亲电弹头，与靶蛋白的亲核残基反应。由于亲电弹头易于与非靶标亲核试剂反应和修饰，因此应仔细平衡其反应性以最大程度地提高靶标选择性。芳基氟硫酸酯最近作为潜伏的亲电试剂出现，可选择性标记蛋白质口袋中特定酪氨酸和赖氨酸残基的上下文。在这里，我们回顾了最近但强烈引入芳基氟硫酸酯作为用于选择性共价修饰蛋白质的可用弹头的情况。我们强调了该官能团在化学生物学和药物发现中的未开发潜力。
