Controlled\nReversible N‑Terminal Modification\nof Peptides and Proteins

A reversible\nmodification strategy enables a switchable cage/decage\nprocess of proteins with an array of applications for protein function\nresearch. However, general N-terminal selective reversible modification\nstrategies which present site selectivity are specifically limited.\nHerein, we report a general reversible modification strategy compatible\nwith 20 canonical amino acids at the N-terminal site by the palladium-catalyzed\ncinnamylation of native peptides and proteins under biologically relevant\nconditions. This approach broadens the substrate adaptability of N-terminal\nmodification of proteins and shows a potential impact on the more\nchallenging protein substrates such as antibodies. In the presence\nof 1,3-dimethylbarbituric acid, palladium-catalyzed deconjugation\nreleased native peptides and proteins efficiently. Harnessing the\nreversible nature of this protocol, practical applications were demonstrated\nby precise function modulation of antibodies and traceless enrichment\nof the protein-of-interest for proteomics analysis. This novel on/off\nstrategy working on the N-terminus will provide new opportunities\nin chemical biology and medicinal research.