Employing Broad Substrate Specificity of Omniligase to Generate Phage-Encoded Bicyclic Peptide Libraries for Ligand Discovery.

We report an enzymatic cyclization strategy termed omniligase-mediated peptide bicyclization. An electrophilic group was introduced into the recognition sequence of omniligase to achieve intramolecular bicyclization with Cys residues. In combination with phage display, we identified a bicyclic peptide ligand targeting TEAD4 with a value of 1.5 μM, 100-fold lower than its linear version, demonstrating the utility of this platform for discovering bicyclic peptide ligands.