LAUSR

ABSTRACT In recent years, the strategy of inhibiting the interactions of p53 with murine double minute 2 (MDM2) and murine double minute X (MDMX) has been proved to be a promising approach for tumor therapy. However, the poor proteolytical stability and low intracellular delivery efficiency of peptide inhibitors limit their clinical application. Here, we designed and synthesized the bicyclic stapled peptides based on p53 by combining all-hydrocarbon stapling and lactam stapling strategies. We demonstrated that bicyclic stapled peptide p53-16 significantly improved α-helicity and proteolytic stability. Especially, p53-16 showed nanomolar binding affinity for MDM2 and MDMX. In addition, p53-16 could penetrate the cell membrane, and selectively inhibited the activity of tumor cells via activating p53 pathway in vitro. Our data suggest that p53-16 is a potential dual inhibitor of MDM2 and MDMX interactions. The bicyclic stapling strategy is a promising drug design strategy for protein–protein interactions inhibitors.