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

Yanbin Ji, Subhabrata Majumder, Melissa Millard, Radhika Borra, Tao Bi, Ahmed Y. Elnagar, Nouri Neamati, Alexander Shekhtman, Julio A. Camarero

Research output: Contribution to journalArticlepeer-review

145 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)11623-11633
Number of pages11
JournalJournal of the American Chemical Society
Volume135
Issue number31
DOIs
StatePublished - Aug 7 2013

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