南开大学陈弓团队报道了通过不同改性乙二醛-赖氨酸二聚体连接剂将两个氨基与各种α-酮醛交联的肽段钉接。相关研究成果发表在2024年2月20日出版的《德国应用化学》。

α-酮醛在普遍存在的蛋白质糖基化的自然过程中发挥着多种作用。然而，利用α-酮醛的反应性进行生物医学应用一直具有挑战性。此前，α-酮醛与胍的反应性已被用于设计在水介质中标记蛋白质上精氨酸残基的探针。

该文描述了一种高效、广泛适用且操作简单的方案，用于通过不同的咪唑连接体将两个氨基与各种α-酮醛试剂交联来钉接天然肽。六氟异丙醇作为溶剂的使用有助于在温和条件下进行快速清洁的反应，并使赖氨酸相对于精氨酸具有独特的选择性。天然存在的GOLD/MOLD连接体已扩展到包括广泛的改性乙二醛赖氨酸二聚体（OLD）连接体。在一项概念验证试验中，这些模块化的钉接反应实现了一种方便的两轮策略，以简化蜂毒肽阿诺林的结构-活性关系（SAR）研究，从而增强生物活性。

附：英文原文

Title: Peptide Stapling via Crosslinking Two Amines with a-Ketoaldehydes through Diverse Modified Glyoxal-Lysine Dimer Linkers

Author: Pan Guo, Xin Chu, Chengjin Wu, Tianjiao Qiao, Wenli Guan, Chuanzheng Zhou, Tao Wang, Changlin Tian, Gang He, Gong Chen

Issue&Volume: 2024-02-20

Abstract: α-Ketoaldehydes play versatile roles in the ubiquitous natural processes of protein glycation. However, leveraging the reactivity of α-ketoaldehydes for biomedical applications has been challenging. Previously, the reactivity of α-ketoaldehydes with guanidine has been harnessed to design probes for labeling Arg residues on proteins in an aqueous medium. Herein, a highly effective, broadly applicable, and operationally simple protocol for stapling native peptides by crosslinking two amino groups through diverse imidazolium linkers with various α-ketoaldehyde reagents is described. The use of hexafluoroisopropanol as a solvent facilitates rapid and clean reactions under mild conditions and enables unique selectivity for Lys over Arg. The naturally occurring GOLD/MOLD linkers have been expanded to encompass a wide range of modified glyoxal-lysine dimer (OLD) linkers. In a proof-of-concept trial, these modular stapling reactions enabled a convenient two-round strategy to streamline the structure-activity relationship (SAR) study of the wasp venom peptide anoplin, leading to enhanced biological activities.

DOI: 10.1002/anie.202318893

Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202318893