title: In vivo activation of the p53 tumor suppressor pathway by an engineered cyclotide.
abstract: The overexpression of Hdm2 and HdmX is a common mechanism used by many tumor cells to inactive the p53 tumor suppressor pathway promoting cell survival. Targeting Hdm2 and HdmX has emerged as a validated therapeutic strategy for treating cancers with wild-type p53. Small linear peptides mimicking the N-terminal fragment of p53 have been shown to be potent Hdm2/HdmX antagonists. The potential therapeutic use of these peptides, however, is limited by their poor stability and bioavailability. Here, we report the engineering of the cyclotide MCoTI-I to efficiently antagonize intracellular p53 degradation. The resulting cyclotide MCo-PMI was able to bind with low nanomolar affinity to both Hdm2 and HdmX, showed high stability in human serum, and was cytotoxic to wild-type p53 cancer cell lines by activating the p53 tumor suppressor pathway both in vitro and in vivo. These features make the cyclotide MCoTI-I an optimal scaffold for targeting intracellular protein-protein interactions.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Yanbin
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Department of Chemistry, State University of New York, Albany, NY 12222, USA.
authors.forename: Subhabrata
authors.initials: S
authors.lastname: Majumder
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Millard
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Radhika
authors.initials: R
authors.lastname: Borra
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Bi
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Ahmed Y
authors.initials: AY
authors.lastname: Elnagar
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
authors.affiliation: Department of Chemistry, State University of New York, Albany, NY 12222, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Shekhtman
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90033, USA.|Department of Chemistry, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Julio A
authors.initials: JA
authors.lastname: Camarero
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D047169:Cyclotides / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008819:Mice, Nude; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015202:Protein Engineering; D060066:Protein Interaction Maps / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D047169:Cyclotides; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2