Merging the Passerini reaction with chemo-enzymatic synthesis for C-terminal peptide modification

Peptide and protein synthesis, as well as bioconjugation, are increasingly important for developing site-selective modifications in biomedical applications. Herein, we report a strategy that combines the Passerini multicomponent reaction and peptiligase-mediated ligations for the selective bio-conjugation of peptide C-termini. The Passerini reaction, performed under aqueous acidic buffer conditions, ensures chemoselectivity for the carboxylic acids, while the subsequent enzymatic ligation selectively targets the functionalized C-terminal substrates. We demonstrated this approach on a diverse set of peptides while incorporating various isocyanides and aldehydes/ketones and successfully achieved ligations. By combining the Passerini reaction with enzymatic selectivity, this method provides a versatile and efficient platform for site-selective C-terminal modification, expanding the toolkit for peptide and protein modifications and synthesis.