Recent progress of chemical methods for lysine site-selective modification of peptides and proteins

Chemical modification of native peptides and proteins is a versatile strategy to facilitate late-stage diversification for functional studies. Among the proteogenic amino acids, lysine is extensively involved in posttranslational modifications and the binding of ligands to target proteins, making its selective modification attractive. However, lysine's high natural abundance and solvent accessibility, as well as its relatively low reactivity to cysteine, necessitate addressing chemoselectivity and regioselectivity for the Lys modification of native proteins. Although Lys chemoselective modification methods have been well developed, achieving site-selective modification of a specific Lys residue remains a great challenge. In this review, we discussed the challenges of Lys selective modification, presented recent examples of Lys chemoselective modification, and summarized the currently known methods and strategies for Lys site-selective modification. We also included an outlook on potential solutions for Lys site-selective labeling and its potential applications in chemical biology and drug development. (c) 2025 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.