Sulfonium is an electrophilic and biocompatible group that is widely applied in synthetic chemistry on small molecules. However, there are few developments of peptide and protein-based sulfonium tools. We recently reported a sulfonium-mediated tryptophan crosslinking, and developed NleS⁺me2 (norleucine-demethylsulfonium) peptides as dimethyllysine mimics that crosslink site-specific methyllysine readers. Therefore, sulfonium probes have great potential to investigate methyllysine readers and other aromatic cage-containing proteins. However, the current synthesis is low efficient and is limited to peptide probes that cannot mimic protein-protein interactions in many cases. In addition to peptidyl conjugate that is valuable for reader identification, there are also unavoidable methyl conjugate as side products. As a result, a robust method to prepare peptide and protein sulfonium tools with great crosslinking reactivity and selectivity is highly desired. Here we report a cysteine alkylation method to introduce site-specific sulfonium at protein level with excellent yield. In addition to dimethylsuofonium, we also developed cyclic sulfonium warheads that enhanced peptidyl conjugate selectivity. The method thus made it possible to prepare nucleosome probe that the LEDGF and NSD2 as H3K36 methylation readers were readily crosslinked. We thus believe this method escalates development of sulfonium peptide and protein tool sets for broad applications in chemical biology study.

中文翻译：

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用于甲基赖氨酸读数仪选择联的磺肽和蛋白质探针的简单制备


磺铵是一种亲电和生物相容性基团，广泛用于小分子的合成化学。然而，基于肽和蛋白质的磺铵工具的发展很少。我们最近报道了一种磺介导的色氨酸交联，并开发了 NleS⁺me2 （去亮氨酸-去甲基磺鎓） 肽作为二甲基赖氨酸模拟物，可交联位点特异性甲基赖氨酸读取器。因此，磺鎓探针在研究甲基赖氨酸读数仪和其他含芳香族笼的蛋白质方面具有巨大潜力。然而，目前的合成效率低，并且仅限于在许多情况下无法模拟蛋白质-蛋白质相互作用的肽探针。除了对读者鉴定有价值的肽基偶联物外，还有不可避免的甲基偶联物作为副产物。因此，非常需要一种稳定的方法来制备具有出色交联反应性和选择性的肽和蛋白质磺工具。在这里，我们报道了一种半胱氨酸烷基化方法，该方法在蛋白质水平上引入位点特异性磺铵，产量极佳。除了二甲基磺铵外，我们还开发了环状磺铵弹头，可增强肽基偶联物的选择性。因此，该方法使得制备核小体探针成为可能，其中 LEDGF 和 NSD2 作为 H3K36 甲基化读数仪很容易交联。因此，我们相信这种方法加快了磺肽和蛋白质工具集的开发，用于化学生物学研究中的广泛应用。