Rewriting lysine reactivity: Lysine-targeted bioconjugation via biomimetic polarity reversal for diversified biomolecule modification

Here, we present a bioinspired oxidative deamination strategy that reverses the polarity of lysine reactivity and thus allows for lysine bioconjugation in peptides and proteins with unprecedented biocompatibility and chemoselectivity. The in-situ-generated aldehyde intermediates facilitate versatile downstream transformations, including ¹⁵N/¹⁸O-labeling, reductive amination, Pinnick oxidation, and Wittig, Seyferth-Gilbert, and Van Leusen reactions. To demonstrate the broad applicability of our strategy, we successfully conjugated diverse functional payloads onto the backbone of semaglutide, full-length proteins, and therapeutic antibodies.