Azaphilones as Activation‐Free Primary‐Amine‐Specific Bioconjugation Reagents for Peptides, Proteins and Lipids

Abstract

AbstractResidue‐selective bioconjugation methods for biomolecules are highly sought to expand the scope of their biological and medical applications. Inspired by the mechanism of the generation of natural vinylogous γ‐pyridones (vPDNs), we have developed a novel unique azaphilone‐based, activation‐free primary‐amine‐selective bioconjugation method for biomolecules. Our strategy allows facile functionalization of primary amine groups in peptides and proteins, including the clinically used therapeutic antibody trastuzumab, by generating a highly stable vPDN linkage. Excellent chemoselectivity toward primary amines also enables the azaphilone derivatives to specifically modify the lipid components of Gram‐positive bacteria while bypassing Gram‐negative bacteria and mammalian cells. The new method shows significant advantages including chemoselectivity, efficiency, flexibility and biocompatibility, and therefore provides a valuable addition to the current toolbox for biomolecule conjugation.