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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.

SUBMITTER: Ji Y 

PROVIDER: S-EPMC3767463 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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In vivo activation of the p53 tumor suppressor pathway by an engineered cyclotide.

Ji Yanbin Y   Majumder Subhabrata S   Millard Melissa M   Borra Radhika R   Bi Tao T   Elnagar Ahmed Y AY   Neamati Nouri N   Shekhtman Alexander A   Camarero Julio A JA  

Journal of the American Chemical Society 20130725 31


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,  ...[more]

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