Journal Article

D-peptide inhibitors of the p53–MDM2 interaction for targeted molecular therapy of malignant neoplasms

Li, Changqing, Wei, Gang, Lv, Yifan, Yuan, Weirong, Gu, Bing, Li, Chong, Zhan, Changyou, Lu, Wei-Yue, Lu, Wuyuan, Liu, Min, Pazgier, Marzena, Mao, Yubin, Gallo, Robert C.

2010

Overview

The oncoproteins MDM2 and MDMX negatively regulate the activity and stability of the tumor suppressor protein p53, conferring tumor development and survival. Antagonists targeting the p53-binding domains of MDM2 and MDMX kill tumor cells both in vitro and in vivo by reactivating the p53 pathway, promising a class of antitumor agents for cancer therapy. Aided by native chemical ligation and mirror image phage display, we recently identified a D-peptide inhibitor of the p53-MDM2 interaction termed D PMI-α (TNWYANLEKLLR) that competes with p53 for MDM2 binding at an affinity of 219 nM. Increased selection stringency resulted in a distinct D-peptide inhibitor termed D PMI-γ (DWWPLAFEALLR) that binds MDM2 at an affinity of 53 nM. Structural studies coupled with mutational analysis verified the mode of action of these D-peptides as MDM2-dependent p53 activators. Despite being resistant to proteolysis, both d PMI-α and d PMI-γ failed to actively traverse the cell membrane and, when conjugated to a cationic cell-penetrating peptide, were indiscriminately cytotoxic independently of p53 status. When encapsulated in liposomes decorated with an integrin-targeting cyclic-RGD peptide, however, d PMI-α exerted potent p53-dependent growth inhibitory activity against human glioblastoma in cell cultures and nude mouse xenograft models. Our findings validate D-peptide antagonists of MDM2 as a class of p53 activators for targeted molecular therapy of malignant neoplasms harboring WT p53 and elevated levels of MDM2.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Amino Acid Sequence / Animal models / Animals / Antagonists / antineoplastic agents / Bacteriophages / binding capacity / Binding sites / Biological Sciences / Cancer / cell culture / Cell Line, Tumor / Cell lines / Cell membranes / Cell Proliferation - drug effects / Cells / Chemotherapy / cytotoxicity / Drug Delivery Systems - methods / Drug Screening Assays, Antitumor / Glioblastoma / Glioblastoma - drug therapy / Glioblastoma - pathology / HCT116 cells / Humans / Ligation / Liposomes / MDM2 protein / mechanism of action / Medical treatment / Mice / Mice, Nude / Mode of action / Mutation / neoplasm cells / neoplasms / Oligopeptides / oncogene proteins / p53 protein / Peptides / Peptides - pharmacology / Peptides - therapeutic use / Phage display / Protein Binding - drug effects / Proteolysis / Proto-Oncogene Proteins c-mdm2 - metabolism / therapeutics / Transplantation, Heterologous / tumor suppressor protein p53 / Tumor Suppressor Protein p53 - metabolism / Tumors / Xenografts