Covalent inhibitors and other types of covalent modalities have seen a revival in the past two decades, with a variety of new targeted covalent drugs having been approved in recent years. A key feature of such molecules is an intrinsically reactive group, typically a weak electrophile, which enables the irreversible or reversible formation of a covalent bond with a specific amino acid of the target protein. This reactive group, often called the “warhead”, is a critical determinant of the ligand’s activity, selectivity, and general biological properties. In 2019, we summarized emerging and re-emerging warhead chemistries to target cysteine and other amino acids (Gehringer, M.; Laufer, S. A. J. Med. Chem. 2019, 62, 5673−5724; DOI: 10.1021/acs.jmedchem.8b01153). Since then, the field has rapidly evolved. Here we discuss the progress on covalent warheads made since our last Perspective and their application in medicinal chemistry and chemical biology.

中文翻译：

---

用于靶向共价抑制剂的新兴和重新出现的弹头：更新

共价抑制剂和其他类型的共价模式在过去二十年中得到复兴，近年来各种新的靶向共价药物已获得批准。此类分子的一个关键特征是本质上的反应基团，通常是弱亲电子试剂，它能够与靶蛋白的特定氨基酸形成不可逆或可逆的共价键。这种反应基团通常称为“弹头”，是配体活性、选择性和一般生物学特性的关键决定因素。 2019 年，我们总结了针对半胱氨酸和其他氨基酸的新兴和重新出现的弹头化学物质（格林格，M .；南澳州劳弗 J. Med。化学。 2019 , 62 , 5673−5724; DOI：10.1021/acs.jmedchem.8b01153）。从那时起，该领域迅速发展。在这里，我们讨论自上一篇观点以来共价弹头的进展及其在药物化学和化学生物学中的应用。