A Dual-Specificity d‑Peptide Antagonist of MDM2 and MDMX for Antitumor Immunotherapy

Designing metabolically stable peptides to target interactions
of the tumor suppressor protein p53 with the two oncogenic proteins
MDM2 and MDMX represents an attractive approach to harvesting “high-hanging
fruits” often inaccessible to traditional anticancer drug discovery
and development efforts. Here, we report the design of a proteolysis-resistant d-dodecapeptide, termed DPMI-ω (EFWYVEp‑ClFEKLLR), capable of disrupting
the p53-MDM2/MDMX complex by antagonizing MDM2 and MDMX. DPMI-ω, upon fabrication on gold nanoparticles, efficiently
traversed tumor cells and killed them by reactivating the p53 signaling
pathway. Further, DPMI-ω inhibited B16 melanoma growth in vivo and, when combined with an anti-PD1 antibody, powerfully
augmented the efficacy of immunotherapy by expanding CD3+/CD8+ cytotoxic T cells and suppressing CD4+/CD25+ regulatory T cells. Our work validates the design
of a therapeutically viable anticancer peptide, showcasing its potential
in combination therapy to treat patients with tumors that are otherwise
resistant or poorly responsive to antitumor immunotherapy.