Azurin-Based Peptide p28 Arrests the p53-HDM2 Interactions: A Novel Anti-Cancer Pathway

Azurin and its derived peptides, notably p28, exhibit significant anticancer properties, primarily by stabilizing the tumor suppressor protein p53 and preventing its degradation. Previous studies have shown that p28 binds to p53's DNA-binding domain, protecting it from degradation mechanisms. Expanding on these findings, our research explored whether p28 acts on additional cancer pathways beyond p53 stabilization. Specifically, we examined the interactions between p28 and Human Double Minute 2 (HDM2), a protein that downregulates p53's tumor-suppressive activity by binding to its transactivation domain (TAD). HDM2 is crucial in diminishing p53's function, and our study aimed to determine if p28 disrupts this HDM2-p53 interaction. Using HADDOCK docking and molecular dynamics simulations, we identified three stable conformations of the HDM2-p28 complex. These conformations effectively block HDM2's hydrophobic pocket, allowing for sustained inter-chain interactions and showing favorable binding energies. Further analysis pinpointed essential residues in these interactions, and we calculated interaction energies using the Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) method. Our findings reveal that by blocking HDM2's binding sites, p28 helps maintain p53's transcriptional activity, thus enhancing its tumor-suppressive functions, including apoptosis and cell cycle arrest in cancer cells. This study enhances understanding of azurin-derived peptides' anticancer mechanisms and highlights p28's potential as a peptide-based anticancer agent. These findings also suggest the possibility of designing additional peptide therapies targeting HDM2 and other cancer-related pathways, opening new directions in anticancer therapeutics.