Jones Lyn H
Dana-Farber Cancer Institute Boston MA USA
Harvard Medical School Boston MA USA.
Chem Sci. 2025 May 6;16(23):10119-10140. doi: 10.1039/d5sc02647d. eCollection 2025 Jun 11.
Targeted covalent inhibitors possess advantages over reversible binding drugs, that include higher potency, enhanced selectivity and prolonged pharmacodynamic duration. The standard paradigm for covalent inhibitor discovery relies on the use of α,β-unsaturated carbonyl electrophiles to engage the nucleophilic cysteine thiol, but due to its rarity in binding sites, the amino acid is often not available for targeting. 10 years ago we highlighted the emerging potential of sulfonyl fluoride chemical probes that were initially found to serendipitously modify residues beyond cysteine, including tyrosine, lysine, histidine, serine and threonine. Since then, the rational application of sulfonyl fluorides and related sulfonyl exchange warheads to site-specifically target diverse amino acid residues in proteins using small molecules, oligonucleotides, peptides and proteins, has made considerable progress, which has significantly advanced covalent therapeutic discovery. Additionally, sulfonyl exchange chemistry has recently shown utility in the labeling of RNA and carbohydrates, further expanding the biomolecular diversity of addressable targets. This Perspective provides not only a timely update regarding this exciting area of research, thus serving as a useful resource to scientists working in the field, but areas of challenge and opportunity are highlighted that may stimulate new research at the chemistry-biology interface.
靶向共价抑制剂相较于可逆结合药物具有诸多优势，包括更高的效力、更强的选择性和更长的药效持续时间。共价抑制剂发现的标准模式依赖于使用α,β-不饱和羰基亲电试剂与亲核半胱氨酸硫醇结合，但由于其在结合位点中较为罕见，该氨基酸通常难以成为靶向目标。十年前，我们强调了磺酰氟化学探针的潜在价值，这类探针最初被发现可意外修饰半胱氨酸以外的残基，包括酪氨酸、赖氨酸、组氨酸、丝氨酸和苏氨酸。从那时起，将磺酰氟及相关的磺酰交换弹头合理应用于使用小分子、寡核苷酸、肽和蛋白质对蛋白质中的不同氨基酸残基进行位点特异性靶向，已经取得了显著进展，这极大地推动了共价治疗药物的发现。此外，磺酰交换化学最近在RNA和碳水化合物标记方面显示出实用性，进一步扩展了可寻址靶标的生物分子多样性。这篇综述不仅及时更新了这一令人兴奋的研究领域的进展，为该领域的科学家提供了有用的资源，还强调了挑战和机遇所在，这可能会激发化学生物学交叉领域的新研究。
