Late-Stage Peptide Modification with Salicylaldehyde Tag Enhances Affinity for Nuclear Factor-kappa B Essential Modulator

Mattia Mason, Kaliroi Peqini, Federico Uggeri, Diego Rondelli, Sara Sattin, Luca Pignataro, Sara Pellegrino, Laura Belvisi, Edoardo Scarpa, Raffaella Bucci and Alberto Dal Corso

RSC Chem. Biol., 2025

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In this work a late-stage peptide functionalization strategy that enables the installation of salicylaldehyde (SA) tags to generate Lys-engaging, reversible-covalent peptide ligands was developed. The strategy was applied to a known binder of NEMO, a key regulator of NFκB signaling. Fluorescence anisotropy assays revealed that several SA-tagged analogues exhibit significantly enhanced affinity compared to the wild-type sequence, consistent with the formation of stabilizing, reversible imine interactions with Lys residues near the peptide-protein interface.

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