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: Yanbin Ji, Subhabrata Majumder, Melissa Millard, Radhika Borra, Tao Bi, Ahmed Y Elnagar, Nouri Neamati, Alexander Shekhtman, Julio A Camarero
• Journal: Journal of the American Chemical Society (J Am Chem Soc) Vol. 135 Issue 31 Pg. 11623-11633 (Aug 07 2013) ISSN: 1520-5126 [Electronic] United States
• PMID: 23848581 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• Cell Cycle Proteins
• Cyclotides
• MDM4 protein, human
• Nuclear Proteins
• Proto-Oncogene Proteins
• Tumor Suppressor Protein p53
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2

Topics

• Amino Acid Sequence
• Animals
• Antineoplastic Agents (chemistry, metabolism, therapeutic use)
• Cell Cycle Proteins
• Cell Line, Tumor
• Cyclotides (chemistry, genetics, therapeutic use)
• Female
• Humans
• Mice, Nude
• Models, Molecular
• Molecular Sequence Data
• Neoplasms (drug therapy)
• Nuclear Proteins (antagonists & inhibitors, metabolism)
• Protein Engineering
• Protein Interaction Maps (drug effects)
• Proto-Oncogene Proteins (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-mdm2 (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)
• Tumor Suppressor Protein p53 (antagonists & inhibitors, chemistry, metabolism)