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.
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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.)
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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
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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)
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