Phage Display of Graspeptides via SrtA-Mediated Peptide Ligation and Cyclization.

We report a chemoenzymatic strategy for generating graspeptide mimetics. This strategy exploits the compatibility of sortase with the ester group at the X position of the pentapeptide sequence (LPXTG). Six types of graspeptide mimetics, including monocyclic and bicyclic depsipeptides, were generated. Combined with phage display, we identified a bicyclic depsipeptide targeting TEAD4 with a KD value of 2.2 μM. This study demonstrates the potential of peptiligase-based system for constructing cyclic peptide libraries with unique topologies.