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Updated: Jul 6, 2025

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Delivery to, and Reactivation of, the p53 Pathway in Cancer Cells Using a Grafted Cyclotide Conjugated with a

Grégoire Jean-Baptiste Philippe1,2, Yen-Hua Huang1, Anna Mittermeier3

  • 1Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Queensland 4072, Australia.

Journal of Medicinal Chemistry
|January 4, 2024
PubMed

Insights

We enhanced peptide drug delivery into cells using a cyclotide scaffold. This improved peptide uptake and activity, enabling modulation of cancer-related protein interactions within the cytosol.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Delivery

Background:

  • Peptides show promise for modulating protein-protein interactions but struggle with intracellular delivery.
  • Targeting intracellular protein-protein interactions is crucial for developing novel therapeutics, especially in cancer treatment.

Purpose of the Study:

  • To improve the cytosolic delivery of peptides that block p53:MDM2/X interactions.
  • To utilize a cyclotide as a stabilizing scaffold for enhanced peptide delivery and efficacy.

Main Methods:

  • Conjugation of a lead cyclotide to a cyclic cell-penetrating peptide (cR10).
  • Assessment of cell internalization, intracellular p53 levels, and apoptosis induction in various cancer cell lines (A549, MCF7, MCF10A).
  • Evaluation of membrane integrity to ensure non-disruptive delivery.

Main Results:

  • Conjugation to cR10 significantly enhanced cell internalization at micromolar concentrations.
  • Elevated intracellular p53 levels were observed in treated cells.
  • The lead peptide demonstrated over 35-fold improvement in inhibitory activity and increased cellular uptake compared to previous analogs.
  • Apoptosis was induced in A549 cells without membrane disruption.

Conclusions:

  • Successful delivery of a large polar cyclic peptide into the cytosol was achieved.
  • The engineered peptide effectively modulates intracellular protein-protein interactions relevant to cancer.
  • This strategy offers a promising approach for developing peptide-based therapeutics targeting intracellular pathways.

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