中国科学院上海药物研究所黄蔚团队报道了多肽和蛋白质的可控可逆N-末端修饰。相关研究成果发表在2024年8月15日出版的《美国化学会杂志》。

可逆的修饰策略实现了蛋白质的可切换笼/衰变过程，为蛋白质功能研究提供了一系列应用。然而，呈现位点选择性的一般N-末端选择性可逆修饰策略受到特别限制。

该文中，研究人员报告了一种通用的可逆修饰策略，该策略在生物相关条件下通过钯催化天然肽和蛋白质的肉桂酰化，在N末端位点与20个典型氨基酸兼容。这种方法拓宽了蛋白质N-末端修饰的底物适应性，并显示出对更具挑战性的蛋白质底物（如抗体）的潜在影响。

在1,3-二甲基巴比妥酸的存在下，钯催化的解偶联有效地释放了天然肽和蛋白质。利用该方案的可逆性，通过精确调节抗体的功能和对蛋白质组学分析中，感兴趣的蛋白质进行无痕富集，证明了其实际应用。这种在N端工作的新型开/关策略，将为化学生物学和医学研究提供新的机会。

附：英文原文

Title: Controlled Reversible N-Terminal Modification of Peptides and Proteins

Author: Zeng Lin, Bo Liu, Mengru Lu, Yongqin Wang, Xuelian Ren, Zhaoxi Liu, Caili Luo, Wei Shi, Xiangman Zou, Xiaohan Song, Feng Tang, He Huang, Wei Huang

Issue&Volume: August 15, 2024

Abstract: A reversible modification strategy enables a switchable cage/decage process of proteins with an array of applications for protein function research. However, general N-terminal selective reversible modification strategies which present site selectivity are specifically limited. Herein, we report a general reversible modification strategy compatible with 20 canonical amino acids at the N-terminal site by the palladium-catalyzed cinnamylation of native peptides and proteins under biologically relevant conditions. This approach broadens the substrate adaptability of N-terminal modification of proteins and shows a potential impact on the more challenging protein substrates such as antibodies. In the presence of 1,3-dimethylbarbituric acid, palladium-catalyzed deconjugation released native peptides and proteins efficiently. Harnessing the reversible nature of this protocol, practical applications were demonstrated by precise function modulation of antibodies and traceless enrichment of the protein-of-interest for proteomics analysis. This novel on/off strategy working on the N-terminus will provide new opportunities in chemical biology and medicinal research.

DOI: 10.1021/jacs.4c04894

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.4c04894