Visible-light-driven C2-phosphonylation of tryptophan in peptides and proteins

Abstract

Tryptophan (Trp) residues are comparatively rare in proteins but are frequently positioned at sites that control folding, molecular recognition, ligand binding, and enzymatic activity. Direct chemical modification of Trp therefore offers a powerful strategy for perturbing protein structure and function. However, methods for installing compact, highly polar functionality onto native Trp residues under mild, protein-compatible conditions remain limited. Here we report a visible-light-driven reductive platform for the C2-selective phosphonylation of Trp-containing peptides and proteins using oxime phosphonates as radical precursors. The reaction proceeds under mild conditions, tolerates diverse peptide sequences containing nearly all proteinogenic amino-acid side chains, and enables late-stage modification of Trp-containing synthetic peptides or peptides derived from structurally complex bioactive molecules. The method further extends to native proteins in aqueous buffer, with LC-MS/MS analysis confirming site-selective modification across a range of protein substrates. Collectively, these results establish photochemical Trp-phosphonylation as a versatile method for peptide diversification, protein conjugation, and chemical control of biomolecular function in situ.