Covalent drugs exert potent and durable activity by chemical modification of the endogenous target protein in vivo. To maximize the pharmacological efficacy while alleviating the risk of toxicity due to nonspecific off-target reactions, current covalent drug discovery focuses on the development of targeted covalent inhibitors (TCIs), wherein a reactive group (warhead) is strategically incorporated onto a reversible ligand of the target protein to facilitate specific covalent engagement. Various aspects of warheads, such as intrinsic reactivity, chemoselectivity, mode of reaction, and reversibility of the covalent engagement, would affect the target selectivity of TCIs. Although TCIs clinically approved to date largely rely on Michael acceptor-type electrophiles for cysteine targeting, a wide array of novel warheads have been devised and tested in TCI development in recent years. In this short review, we provide an overview of recent progress in chemistry for selective covalent targeting of proteins and their applications in TCI designs.

共价药物通过在体内对内源性靶蛋白进行化学修饰而发挥有效和持久的活性。为了最大限度地提高药理功效，同时减轻由于非特异性脱靶反应引起的毒性风险，目前的共价药物发现重点是开发靶向共价抑制剂（TCI），其中反应基团（弹头）战略性地结合到可逆配体上靶蛋白以促进特定的共价结合。弹头的各个方面，例如内在反应性、化学选择性、反应模式和共价结合的可逆性，都会影响 TCI 的目标选择性。尽管迄今为止临床批准的 TCI 在很大程度上依赖于迈克尔受体型亲电子试剂来靶向半胱氨酸，近年来，在 TCI 开发中设计并测试了多种新型弹头。在这篇简短的综述中，我们概述了蛋白质选择性共价靶向化学的最新进展及其在 TCI 设计中的应用。