Screening of Modular Self‐Assembling Peptides for Targeting the MDM2 Protein

The MDM2-p53 signaling axis governs the homeostatic balance between cell proliferation and apoptosis, and its aberrant activation drives tumor onset and progression. Disruption of this pathway therefore represents an effective strategy to suppress malignant growth. Here, the one-bead one-compound (OBOC) peptide library is designed to identify self-assembling peptide leads that specifically target MDM2. Differently from conventional static inhibitory peptides, the identified peptides exhibit unique target-triggered self-assembly behavior upon specific binding to MDM2 protein. The peptides first bind MDM2 with high nanomolar affinity and subsequently assemble into dense nanofibrous structures in situ, which sterically and efficiently disrupt the MDM2-p53 interaction. In vitro cellular assays demonstrate that these self-assembled peptide nanofibers remarkably suppress tumor cell proliferation and migration. Collectively, this work discovers a novel class of MDM2-targeting peptides with programmable self-assembly property, providing an innovative structural design strategy and promising precursor candidates for future MDM2-p53 pathway-targeted antitumor research.