Late-Stage Functionalization of Lysine to Organelle-Targeting Fluorescent Probes

The late-stage functionalization of peptides presents a promising avenue for expanding their chemical diversity and properties, particularly in the realm of drug discovery. Herein, we present a powerful late-stage functionalization (LSF) strategy for peptides that includes an addition-cyclization-aromatization (ACA) transformation to generate 2,3,4,6-substituted pyridinium, with inherent fluorescence, specifically at lysine residues. This method enables the precise and irreversible labeling of diverse peptide sequences, both in solution and on solid support, with quantum yields ranging from 0.02 to 0.03. Importantly, the 2,3,4,6-substituted pyridinium core represents a delocalized lipophilic cation (DLC), exhibiting strong mitochondrial-targeting properties. This unique platform facilitates real-time imaging and targeted delivery of drugs and peptides to mitochondria without the need for additional tagging, offering significant potential for theranostic applications.