Covalent inhibitors are widely used in drug discovery and chemical biology. Although covalent inhibitors are frequently designed to react with noncatalytic cysteines, many ligand binding sites lack an accessible cysteine. Here, we review recent advances in the chemical biology of lysine-targeted covalent inhibitors and chemoproteomic probes. By analyzing crystal structures of proteins bound to common metabolites and enzyme cofactors, we identify a large set of mostly unexplored lysines that are potentially targetable with covalent inhibitors. In addition, we describe mass spectrometry-based approaches for determining proteome-wide lysine ligandability and lysine-reactive chemoproteomic probes for assessing drug-target engagement. Finally, we discuss the design of amine-reactive inhibitors that form reversible covalent bonds with their protein targets.

中文翻译：

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赖氨酸靶向抑制剂和化学旋转探针。

共价抑制剂广泛用于药物发现和化学生物学。尽管通常将共价抑制剂设计为与非催化性半胱氨酸反应，但许多配体结合位点缺少可及的半胱氨酸。在这里，我们回顾了赖氨酸靶向共价抑制剂和化学旋转探针化学生物学的最新进展。通过分析与常见代谢物和酶辅因子结合的蛋白质的晶体结构，我们确定了一大批未开发的赖氨酸，它们可能通过共价抑制剂靶向。此外，我们描述了基于质谱的方法来确定蛋白质组范围内的赖氨酸配体能力和赖氨酸反应性化学旋转探针，以评估药物靶标的参与。最后，