Sulfur(IV) Chemistry-Based Peptide and Protein Late-Stage Modification

The development of precise and controllable chemical modification tools for peptides and proteins represents a great challenge in elucidating their structure-activity relationships and regulatory mechanisms, as well as a powerful driver for advancing macromolecular therapeutic strategies. However, current technologies predominantly rely on irreversible covalent labeling or genetic encoding of unnatural amino acids, exhibiting significant limitations in reversible modification, in situ functional regulation, and adaptability to complex physiological environments. In recent years, breakthrough advancements in sulfur(IV) chemistry have provided a paradigm for the late-stage functionalization of peptides and proteins. Through synergistic innovations in sulfur(IV)-based reagent design, intermediate modulation, and bioorthogonal reactions, a more multifaceted modification toolbox has been progressively established, integrating site selectivity, condition responsiveness, and functional rescue. Providing current challenges and future perspectives in this field, this review focuses on sulfur(IV) chemistry-driven strategies for peptide and protein modification, as well as their applications in proximity-labeling strategies and drug delivery/therapeutic interventions.