近日，美国南佛罗里达大学
为了克服这些限制，研究人员开发了一个模块化的硫（IV）试剂平台，用于磺酰基和磺酰基-双环丁烷基序的轻度、后期安装，具有完全的半胱氨酸选择性。该方法可以获得具有可调菌株释放反应性的多种硫（VI） CRGs。与美国食品和药物管理局批准的共价抑制剂结合，证明了丙烯酰胺的有效生物等甾体替代，以及菌株释放CRG选择性靶向蛋白质的潜力。小鼠的临床前研究证实了这种方法，突出了它在下一代共价药物设计方面的前景。
研究人员表示，在治疗和化学生物学领域，共价抑制作为一种选择性蛋白质调节的策略继续获得势头。共价反应基团（CRGs）通常参与亲核残基，如半胱氨酸，导致靶向蛋白失活。然而，常见的亲电试剂如丙烯酰胺往往具有非选择性反应性，导致脱靶效应和毒性。
附：英文原文
Title: Late-stage functionalization with strain-release warheads enables tunable covalent inhibition
Author: Zachary P. Shultz, Ansar Lee-Sam, Yun-Pu Chang, Luxin Sun, Dylan Grassie, Alessio Gabellini, Kyle Pedretty, Thomas Scattolin, Victoria Izumi, Bin Fang, Samer Sansil, Ramu Kakumanu, Lukasz Wojtas, John Koomen, Ernst Schnbrunn, Andrii Monastyrskyi, Derek Duckett, Justin M. Lopchuk
Issue&Volume: 2026-07-23
Abstract: Covalent inhibition continues to gain momentum as a strategy for selective protein modulation in both therapeutic and chemical biology contexts. Covalent reactive groups (CRGs) typically engage nucleophilic residues such as cysteine, resulting in targeted protein inactivation. However, common electrophiles such as acrylamides often suffer from nonselective reactivity, leading to off-target effects and toxicity. To overcome these limitations, we developed a modular sulfur(IV) reagent platform for the mild, late-stage installation of sulfonyl- and sulfonimidoyl-bicyclobutane motifs with complete cysteine selectivity. This methodology enables access to diverse sulfur(VI) CRGs with tunable strain-release reactivity. Incorporation into US Food and Drug Administration–approved covalent inhibitors demonstrated effective bioisosteric replacement of acrylamides and the potential of strain-release CRGs for selective protein targeting. Preclinical studies in mice have validated this approach, highlighting its promise for next-generation covalent drug design.
DOI: adx7219
Source: https://www.science.org/doi/10.1126/science.adx7219