Reversible stapling of unprotected peptides via chemoselective methionine bis-alkylation/dealkylation

We have developed a general peptide macrocyclization strategy that involves a facile and chemoselective methionine bis-alkylation/dealkylation process. This method provides a straightforward and easy approach to generate cyclic peptides with tolerances of all amino acids (including Cys), variable loop sizes, and different linkers. The Met bis-alkylation we apply in this strategy yields two additional on-tether positive charges that could assist in the cellular uptake of the peptides. Notably, the bis-alkylated peptide could be reduced to release the original peptide both in vitro and within cellular environments. This strategy provides an intriguing and facile traceless post-peptide-synthesis modification with enhanced cellular uptakes. Peptides constructed with this method could be utilized to zero in on various protein targets or to achieve other goals, such as drug delivery.