Diazaborine-Mediated Bicyclization of Native Peptides with Inducible Reversibility

Multicyclic Peptides are appealing candidates for peptide-based drug discovery. While various methods are developed for peptide cyclization, few allow multicyclization of native Peptides. Herein we report a novel cross-linker DCA-RMR1, which elicits facile bicyclization of native Peptides via N-terminus Cys-Cys cross-linking. The bicyclization is fast, affords quantitative conversion, and tolerates various side chain functionalities. Importantly, the resulting diazaborine linkage, while stable at a neutral pH, can readily reverse upon mild acidification to give pH-responsive Peptides.