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Updated: May 16, 2026

Construction of Cyclic Cell-Penetrating Peptides for Enhanced Penetration of Biological Barriers
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Construction of Cyclic Cell-Penetrating Peptides for Enhanced Penetration of Biological Barriers

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Stapled peptides with improved potency and specificity that activate p53.

Christopher J Brown1, Soo T Quah, Janice Jong

  • 1p53 Laboratory (p53Lab, A*STAR), 8A Biomedical Grove, #06-06, Immunos, Singapore 138648. cjbrown@p53lab.a-star.edu.sg

ACS Chemical Biology
|December 11, 2012
PubMed
Summary
This summary is machine-generated.

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New compounds targeting Mdm2/Mdm4, derived from phage display peptides, show enhanced p53 activation and protein interaction. These Mdm2/Mdm4 inhibitors are effective in resistant cells without toxicity, suggesting potential for cyclotherapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Mdm2 and Mdm4 are key negative regulators of the tumor suppressor p53.
  • Inhibiting Mdm2/Mdm4 interactions can restore p53 function, offering a therapeutic strategy for cancer.
  • Existing inhibitors like Nutlin have limitations in certain resistant cell populations.

Purpose of the Study:

  • To develop novel compounds targeting Mdm2/Mdm4 with improved efficacy and safety profiles.
  • To evaluate the potency of phage-derived compounds in activating p53 and inhibiting protein-protein interactions.
  • To assess the therapeutic potential of these compounds in p53-resistant cancer cells.

Main Methods:

  • Phage display technology was used to identify peptide templates targeting Mdm2/Mdm4.

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Last Updated: May 16, 2026

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Construction of Cyclic Cell-Penetrating Peptides for Enhanced Penetration of Biological Barriers

Published on: September 19, 2022

Constructing Thioether/Vinyl Sulfide-tethered Helical Peptides Via Photo-induced Thiol-ene/yne Hydrothiolation
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Constructing Thioether/Vinyl Sulfide-tethered Helical Peptides Via Photo-induced Thiol-ene/yne Hydrothiolation

Published on: August 1, 2018

  • Peptide templates were optimized into small molecule compounds.
  • In vitro assays were performed to measure p53 activation and Mdm2/Mdm4 protein-protein interaction inhibition.
  • Cellular assays assessed apoptosis, cell cycle arrest, and toxicity in various cancer cell lines, including those resistant to p53-induced apoptosis.

    • Main Results:

    • Phage display-derived compounds demonstrated high specificity for Mdm2/Mdm4.
    • These compounds exhibited superior potency in p53 activation and protein-protein interaction assays compared to p53 wild-type derived compounds.
    • Unlike Nutlin, the phage-derived compounds effectively arrested cells resistant to p53-induced apoptosis across a broad concentration range.
    • No significant cellular toxicity was observed with the phage-derived compounds.

    Conclusions:

    • Phage display is a viable strategy for generating potent Mdm2/Mdm4 inhibitors.
    • The novel compounds show promise as effective therapeutic agents for cancers with Mdm2/Mdm4 overexpression or p53 pathway dysregulation.
    • The lack of toxicity and efficacy in resistant cells suggests suitability for cyclotherapy applications.