Trifluoroacetic Acid Promotes Ultrafast Peptide Cyclization Mediated with Dimethylolurea

Cyclic peptides have gained widespread attention as potential medium-sized modulators of biomolecular interactions with large binding surfaces. Effective and user-friendly cyclization methods are increasingly becoming important for researchers across disciplines seeking to access diverse cyclic peptide structures. Here, a highly selective, rapid, and operationally simple method is reported for directly cyclizing unprotected peptides in which dimethylolurea effectively reacts with a pair of cysteine residues within an unprotected peptide sequence, forming a novel cyclic peptide. The reaction occurs in a trifluoroacetic acid-acetonitrile-water system, offering rapid conversion and easy operation. Furthermore, we demonstrate the applicability of dimethylolurea-mediated cyclization to generate cyclic peptides with improved uptake into living cells and enhanced affinity for their target proteins. Overall, this method provides a valuable addition to the peptide engineering toolbox, facilitating the development of functional cyclic peptides for chemical biology and drug discovery.