Recent Advances in Selective Modification of Tryptophan Residues in Peptides: From Site Functionalization to Skeletal Editing

Tryptophan (Trp) is a low-abundance amino acid whose indole side chain contributes to molecular recognition, membrane association and protein–protein interactions. These roles make Trp a useful target for late-stage peptide modification, but they also create a risk of changing peptide function. This review examines representative methods published in 2024–2026, with earlier studies providing context. The discussion covers N1 and C2 functionalization, β-position modification, oxidative cyclization, indole-to-quinazoline editing, remote functionalization and enzymatic reactions. Methods are compared by substrate protection, preinstalled groups, reaction medium, selectivity and yield measurement. Recent advances include direct changes to the indole skeleton, labeling in neutral buffer and living cells, and enzyme-catalyzed modification followed by chemical coupling. Functional studies show both benefits and losses: selected modifications improve serum stability or antibacterial activity, whereas others reduce potency or receptor affinity. Key challenges are to distinguish multiple Trp residues in one peptide, confirm product structure, assess linkage stability and preserve the required biological function. These comparisons support method selection for peptide synthesis, labeling and property optimization.