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

作者：Liu, Min; Li, Chong; Pazgier, Marzena; Li, Changqing; Mao, Yubin; Lv, Yifan; Gu, Bing; Wei, Gang; Yuan, Weirong; Zhan, Changyou; Lu, Wei-Yue; Lu, Wuyuan

来源：Proceedings of the National Academy of Sciences, 2010, 107(32): 14321-14326.

DOI：10.1073/pnas.1008930107

• mirror-image phage display
• native chemical ligation
• glioblastoma

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 (PMI)-P-D-alpha (TNWYAN-LEKLLR) that competes with p53 for MDM2 binding at an affinity of 219 nM. Increased selection stringency resulted in a distinct D-peptide inhibitor termed (PMI)-P-D-gamma (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 (PMI)-P-D-alpha and (PMI)-P-D-gamma 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, (PMI)-P-D-alpha 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.

• 出版日期2010-8-10
• 单位复旦大学