Synthesis of DNA-Encoded Bicyclic Peptides via Cysteine-Promoted Cyclization and Amide Condensation Reaction

Bicyclic peptides, with two cyclic substructures, have emerged as a powerful tool for modulating challenging targets such as protein-protein interactions. Meanwhile, DNA-encoded library technology (DELT) provides a powerful platform for hit discovery. The unity of both fields has the potential to identify potent bicyclic ligands for the targets of interest. Therefore, there is a high demand to develop an efficient way to construct bicyclic peptide libraries. Herein, we describe a novel and efficient approach to the synthesis of DNA-encoded bicyclic peptides via a cysteine-promoted cyclization and amide condensation reaction. This strategy proceeds smoothly under mild conditions and can generate a wide range of bicyclic peptides with various peptide sequences and ring sizes in good conversions.