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.

着眼于扩展用于共价配体发现的化学方法，我们详细阐述了一种umpolung策略，该策略利用半胱氨酸被氧化为次磺酸时硫的“极性反转”（一种广泛的翻译后修饰），用于与C-亲核试剂选择性生物缀合。在这里，我们展示了人类亚磺基的全局图谱，该亚磺基易于被亲核片段库的成员共价修饰。在不同功能类别的蛋白质上鉴定出 500 多种配体次磺酸，其中 80% 以上不是亲电片段类似物的靶向。我们进一步表明，我们的亲核片段库的成员可以损害参与核癌蛋白运输和 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效用，预示着使用非传统化学来靶向蛋白质的进一步机会。