With an eye toward expanding chemistries used for covalent ligand discovery, we elaborated an umpolung strategy that exploits the ‘polarity reversal’ of sulfur when cysteine is oxidized to sulfenic acid, a widespread post-translational modification, for selective bioconjugation with C-nucleophiles. Here we present a global map of a human sulfenome that is susceptible to covalent modification by members of a nucleophilic fragment library. More than 500 liganded sulfenic acids were identified on proteins across diverse functional classes, and, of these, more than 80% were not targeted by electrophilic fragment analogs. We further show that members of our nucleophilic fragment library can impair functional protein–protein interactions involved in nuclear oncoprotein transport and DNA damage repair. Our findings reveal a vast expanse of ligandable sulfenic acids in the human proteome and highlight the utility of nucleophilic small molecules in the fragment-based covalent ligand discovery pipeline, presaging further opportunities using non-traditional chemistries for targeting proteins.

着眼于扩大用于共价配体发现的化学成分，我们制定了一种 umpolung 策略，该策略利用半胱氨酸被氧化成亚磺酸（一种广泛的翻译后修饰）时硫的“极性反转”，与 C 核试剂进行选择性生物偶联。在这里，我们展示了人磺烯组的整体图谱，该表易受亲核片段文库成员的共价修饰。在不同功能类别的蛋白质上鉴定出 500 多种配体亚磺酸，其中 80% 以上未被亲电片段类似物靶向。我们进一步表明，我们的亲核片段文库的成员可以损害参与核癌蛋白转运和 DNA 损伤修复的功能性蛋白质-蛋白质相互作用。我们的研究结果揭示了人类蛋白质组中大量可配体的亚磺酸，并强调了亲核小分子在基于片段的共价配体发现管道中的实用性，预示着使用非传统化学靶向蛋白质的进一步机会。