title: D-peptide inhibitors of the p53-MDM2 interaction for targeted molecular therapy of malignant neoplasms.
abstract: 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-alpha (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-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 (D)PMI-alpha and (D)PMI-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, (D)PMI-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.
authors.affiliation: Institute of Human Virology and Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.forename: Chong
authors.initials: C
authors.lastname: Li
authors.forename: Marzena
authors.initials: M
authors.lastname: Pazgier
authors.forename: Changqing
authors.initials: C
authors.lastname: Li
authors.forename: Yubin
authors.initials: Y
authors.lastname: Mao
authors.forename: Yifan
authors.initials: Y
authors.lastname: Lv
authors.forename: Bing
authors.initials: B
authors.lastname: Gu
authors.forename: Gang
authors.initials: G
authors.lastname: Wei
authors.forename: Weirong
authors.initials: W
authors.lastname: Yuan
authors.forename: Changyou
authors.initials: C
authors.lastname: Zhan
authors.forename: Wei-Yue
authors.initials: WY
authors.lastname: Lu
authors.forename: Wuyuan
authors.initials: W
authors.lastname: Lu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods; D004354:Drug Screening Assays, Antitumor; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008081:Liposomes; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D008081:Liposomes; D009842:Oligopeptides; D010455:Peptides; D016159:Tumor Suppressor Protein p53; C047981:arginyl-glycyl-aspartic acid; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2