Sulfur electrophiles constitute an important class of covalent small molecules that have found widespread applications in synthetic chemistry and chemical biology. Various electrophilic scaffolds, including sulfonyl fluorides and arylfluorosulfates as recent examples, have been applied for protein bioconjugation to probe ligand sites amenable for chemical proteomics and drug discovery. In this review, we describe the development of sulfonyl-triazoles as a new class of electrophiles for sulfur–triazole exchange (SuTEx) chemistry. SuTEx achieves covalent reaction with protein sites through irreversible modification of a residue with an adduct group (AG) upon departure of a leaving group (LG). A principal differentiator of SuTEx from other chemotypes is the selection of a triazole heterocycle as the LG, which introduces additional capabilities for tuning the sulfur electrophile. We describe the opportunities afforded by modifications to the LG and AG alone or in tandem to facilitate nucleophilic substitution reactions at the SO₂ center in cell lysates and live cells. As a result of these features, SuTEx serves as an efficient platform for developing chemical probes with tunable bioactivity to study novel nucleophilic sites on established and poorly annotated protein targets. Here, we highlight a suite of biological applications for the SuTEx electrophile and discuss future goals for this enabling covalent chemistry.

中文翻译：

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硫三唑交换（SuTEx）化学的发展和生物应用

硫亲电试剂构成一类重要的共价小分子，已在合成化学和化学生物学中得到广泛应用。各种亲电子支架，包括磺酰氟和芳基氟硫酸盐作为最近的例子，已被应用于蛋白质生物偶联，以探测适合化学蛋白质组学和药物发现的配体位点。在这篇综述中，我们描述了磺酰基-三唑类作为硫-三唑交换（SuTEx）化学的一类新型亲电试剂的发展。SuTEx 通过在离去基团 (LG) 离开后用加合物基团 (AG) 对残基进行不可逆修饰来实现与蛋白质位点的共价反应。SuTEx 与其他化学型的主要区别在于选择三唑杂环作为 LG，它引入了额外的功能来调整硫亲电子试剂。我们描述了单独或串联修改 LG 和 AG 所提供的机会，以促进 SO 处的亲核取代反应₂细胞裂解物和活细胞的中心。由于这些特性，SuTEx 可作为开发具有可调生物活性的化学探针的有效平台，以研究已建立和注释不佳的蛋白质靶标上的新型亲核位点。在这里，我们重点介绍了 SuTEx 亲电试剂的一套生物学应用，并讨论了这种实现共价化学的未来目标。