Resurrecting a p53 peptide activator - An enabling nanoengineering strategy for peptide therapeutics

J Control Release. 2020 Sep 10:325:293-303. doi: 10.1016/j.jconrel.2020.06.041. Epub 2020 Jul 10.

Abstract

Many high-affinity peptide antagonists of MDM2 and MDMX have been reported as activators of the tumor suppressor protein p53 with therapeutic potential. Unfortunately, peptide activators of p53 generally suffer poor proteolytic stability and low membrane permeability, posing a major pharmacological challenge to anticancer peptide drug development. We previously obtained several potent dodecameric peptide antagonists of MDM2 and MDMX termed PMIs, one of which, TSFAEYWALLSP, bound to MDM2 and MDMX at respective affinities of 0.49 and 2.4 nM. Here we report the development of gold nanoparticles (Np) as a membrane-traversing delivery vehicle to carry PMI for anticancer therapy. Np-PMI was substantially more active in vitro than Nutlin-3 in killing tumor cells bearing wild-type p53, and effectively inhibited tumor growth in metastasis in a mouse homograft mode of melanoma and a patient-derived xenograft model of colon cancer with a favorable safety profile. This clinically viable drug delivery strategy can be applied not only to peptide activators of p53 for cancer therapy, but also to peptide therapeutics in general aimed at targeting intracellular protein-protein interactions for disease intervention.

Keywords: MDM2; MDMX; Nanoparticle; Peptide therapeutics; Protein-protein interaction; p53.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Cycle Proteins
  • Gold
  • Metal Nanoparticles*
  • Mice
  • Peptides / metabolism
  • Proto-Oncogene Proteins c-mdm2* / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Cell Cycle Proteins
  • Peptides
  • Tumor Suppressor Protein p53
  • Gold
  • Proto-Oncogene Proteins c-mdm2