Tyrosine-Selective Polyfluoroaryl Modification Enables Bioactive Peptides with Enhanced Membrane Permeability and Ligation Capability

We report a tyrosine-selective polyfluoroaryl modification strategy using tetrafluoro-substituted N-methyl luminol reagents. Under mild oxidative conditions, this platform achieves rapid and chemoselective functionalization of Tyr residues across diverse bioactive peptides. The installed tetrafluoroaryl motif serves as a versatile handle for linker-free peptide–peptide ligation via SNAr with N-terminal cysteines, as confirmed by 19F NMR and X-ray crystallography. Furthermore, this modification significantly enhances the membrane permeability of cell-penetrating peptides, enabling the cytosolic delivery of macromolecular cargos. This work provides a unified workflow for peptide fluorination, programmable ligation, and physicochemical optimization.