Some of the most widely used drugs, such as aspirin and penicillin, are covalent drugs. Covalent binding can improve potency, selectivity, and duration of the effects, but the intrinsic reactivity represents a potential liability and may result in idiosyncratic toxicity. For decades, the cons were believed to outweigh the pros, and covalent targeting was deprioritized in drug discovery. Recently, several covalent inhibitors have been approved for cancer treatment, thus rebooting the field. In this review, we briefly reflect on the history of selective covalent targeting, and provide a comprehensive overview of emerging developments from a chemical biology stand-point. Our discussion will reflect on efforts to validate irreversible covalent ligands, expand the scope of targets, and discover new ligands and warheads. We conclude with a brief commentary of remaining limitations and emerging opportunities in selective covalent targeting.

中文翻译：

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选择性和不可逆共价配体的开发和验证的最新进展。

一些最广泛使用的药物，例如阿司匹林和青霉素，是共价药物。共价结合可以提高效力，选择性和作用持续时间，但内在反应性代表潜在的责任并可能导致特异毒性。几十年来，人们一直认为缺点超过了优点，在药物开发中优先考虑了共价靶向。最近，已经批准了几种共价抑制剂用于癌症治疗，从而重新启动了该领域。在这篇综述中，我们简要回顾了选择性共价靶向的历史，并从化学生物学的角度全面概述了新兴的发展。我们的讨论将反思验证不可逆共价配体，扩大目标范围以及发现新的配体和战斗部的努力。