Peptide macrocycles have become a powerful platform for exploring new chemical spaces in drug discovery. While significant progress has been made in chemistry for cyclizing pre-engineered peptide substrates equipped with exogenous reactive groups, methods capable of stapling native peptides through their endogenous side chains are much underexplored. Presently, the strategies for stapling native peptides predominantly revolve around the reactivity of cysteine (Cys). To broaden the toolkit, peptide modification techniques that selectively target non-Cys α amino acid (AA) residues are pressingly needed α-Ketoaldehydes play versatile roles in the ubiquitous natural processes of protein glycation. However, leveraging the reactivity of α-ketoaldehydes for biomedical applications has been challenging. Previously, the reactivity of α-ketoaldehydes with guanidine has been harnessed to design probes for labeling Arg residues on proteins in an aqueous medium.

Recently, Gong Chen’s group have a developed a highly effective, broadly applicable, and operationally simple protocol for stapling native peptides by crosslinking two amino groups through diverse imidazolium linkers with various α-ketoaldehyde reagents. The use of hexafluoroisopropanol as a solvent facilitates rapid and clean reactions under mild conditions and enables unique selectivity for Lys over Arg. The naturally occurring GOLD/MOLD linkers have been expanded to encompass a wide range of modified glyoxal-lysine dimer (OLD) linkers. In a proof-of-concept trial, these modular stapling reactions enabled a convenient two-round strategy to streamline the structure–activity relationship (SAR) study of the wasp venom peptide anoplin, leading to enhanced biological activities. Relevant achievements were published in Angew. Chem. Int. Ed., 2024, DOI: 10.1002/anie.202318893.