Triazine Linchpins for Selective Lys-Lys Stapling of Unprotected Peptides

Peptide stapling exerts profound effects on key peptide properties, including metabolic stability, cell membrane permeability, and conformational constraint. Herein, we report a mild and efficient 2,4-dichloro-1,3,5-triazine-mediated stapling strategy for the selective cross-linking of lysine side-chain amines. This approach furnishes macrocyclic peptides of varying ring sizes. This method features broad functional group compatibility with most natural amino acid residues (His, Trp, Arg, Tyr, Ser and Thr), as well as N-terminal α-amino and C-terminal carboxylate moieties, whereas cysteine is not tolerated in this transformation. For the representative stapled macrocyclic peptides, the 1,3,5-triazine bridge significantly enhanced proteolytic stability, membrane permeability and helical propensity, and potentiated their antiproliferative activity against multiple cancer cell lines.