School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou, 310024, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No.555 Zuchongzhi Rd, Pudong, Shanghai, 201203, China.
Angew Chem Int Ed Engl. 2024 Apr 15;63(16):e202401394. doi: 10.1002/anie.202401394. Epub 2024 Mar 11.
Carbohydrates play pivotal roles in an array of essential biological processes and are consequently involved in many diseases. To meet the needs of glycobiology research, chemical enzymatic and non-enzymatic methods have been developed to generate glycoconjugates with well-defined structures. Herein, harnessing the unique properties of C6-oxidized glycans, we report a straightforward and robust strategy for site- and stereoselective glycomodification of biomolecules with N-terminal tryptophan residues by a carbohydrate-promoted Pictet-Spengler reaction, which is not adapted to typical aldehyde substrates under biocompatible conditions. This method reliably delivers highly homogeneous glycoconjugates with stable linkages and thus has great potential for functional modulation of peptides and proteins in glycobiology research. Moreover, this reaction can be performed at the glycosites of glycopeptides, glycoproteins and living-cell surfaces in a site-specific manner. Control experiments indicated that the protected α-O atom of aldehyde donors and free N-H bond of the tryptamine motif are crucial for this reaction. Mechanistic investigations demonstrated that the reaction exhibited a first-order dependence on both tryptophan and glycan, and deprotonation/rearomatization of the pentahydro-β-carbolinium ion intermediate might be the rate-determining step.
碳水化合物在一系列重要的生物过程中起着关键作用，因此与许多疾病有关。为了满足糖生物学研究的需求，已经开发出了化学酶法和非酶法来生成具有明确结构的糖缀合物。在此，利用 C6-氧化聚糖的独特性质，我们报告了一种在生物相容性条件下通过糖促进的 Pictet-Spengler 反应对具有 N 端色氨酸残基的生物分子进行位点和立体选择性糖基化修饰的简单而稳健的策略，该方法不适用于典型的醛类底物。该方法可靠地提供了具有稳定键的高度均一的糖缀合物，因此在糖生物学研究中对肽和蛋白质的功能调节具有很大的潜力。此外，该反应可以在糖肽、糖蛋白和活细胞表面的糖基位点以位点特异性的方式进行。对照实验表明，醛供体的保护 α-O 原子和色胺基序的游离 N-H 键对于该反应至关重要。机理研究表明，该反应对色氨酸和聚糖均表现出一级依赖关系，并且五氢-β-咔啉翁中间体的去质子化/再芳构化可能是速率决定步骤。
