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Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

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

Yanbin Ji1, Subhabrata Majumder2, Melissa Millard1

  • 1Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90033, USA.

Journal of the American Chemical Society
|July 16, 2013
PubMed

Insights

Engineered cyclotides target Hdm2 and HdmX, inhibiting cancer cell survival. This novel MCo-PMI peptide shows stability and efficacy against wild-type p53 tumors, offering a promising cancer therapy.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Hdm2 and HdmX overexpression inactivates the p53 tumor suppressor pathway in cancer cells.
  • Targeting Hdm2/HdmX is a therapeutic strategy for wild-type p53 cancers.
  • Linear peptides mimicking p53 are potent Hdm2/HdmX antagonists but have poor stability and bioavailability.

Purpose of the Study:

  • To engineer the cyclotide MCoTI-I as a stable and bioavailable antagonist of Hdm2/HdmX for cancer therapy.
  • To evaluate the efficacy of the engineered cyclotide MCo-PMI in antagonizing p53 degradation and its cytotoxic effects on cancer cells.

Main Methods:

  • Engineering the cyclotide MCoTI-I scaffold to create MCo-PMI.
  • Assessing MCo-PMI binding affinity to Hdm2 and HdmX.
  • Evaluating MCo-PMI stability in human serum.
  • Testing MCo-PMI's cytotoxicity and p53 pathway activation in wild-type p53 cancer cell lines in vitro and in vivo.

Main Results:

  • Engineered cyclotide MCo-PMI demonstrated low nanomolar binding affinity to both Hdm2 and HdmX.
  • MCo-PMI exhibited high stability in human serum.
  • MCo-PMI was cytotoxic to wild-type p53 cancer cell lines.
  • MCo-PMI activated the p53 tumor suppressor pathway both in vitro and in vivo.

Conclusions:

  • The cyclotide MCoTI-I is an effective scaffold for developing Hdm2/HdmX antagonists.
  • MCo-PMI represents a promising therapeutic candidate for treating cancers with wild-type p53 by stabilizing the p53 pathway.
  • Engineered cyclotides can overcome the limitations of linear peptides for targeting intracellular protein-protein interactions.

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