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Updated: Aug 1, 2025

Oligopeptide Competition Assay for Phosphorylation Site Determination
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Stapled Peptides as Direct Inhibitors of Nrf2-sMAF Transcription Factors

Ramya Modi1, Nick McKee2, Ning Zhang2

  • 1Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States.

Journal of Medicinal Chemistry
|April 25, 2023
PubMed

Insights

A novel stapled peptide, N1S, directly inhibits the Nrf2/sMAF protein interaction. This peptide reduces cancer cell survival and sensitizes them to chemotherapy, offering a new therapeutic strategy for Nrf2-addicted cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Nuclear factor erythroid-related 2-factor 2 (Nrf2) is a transcription factor crucial for cellular protection.
  • Constitutive Nrf2 activation in cancer promotes therapeutic resistance by upregulating target genes.
  • Nrf2 interacts with small musculoaponeurotic fibrosarcoma Maf (sMAF) proteins to bind DNA and drive gene transcription.

Purpose of the Study:

  • To develop and characterize the first cell-permeable inhibitor targeting the Nrf2/sMAF heterodimerization.
  • To evaluate the efficacy of the inhibitor in disrupting Nrf2 transcriptional activity and sensitizing cancer cells.

Main Methods:

  • Design of a stapled peptide inhibitor (N1S) based on AlphaFold structural predictions of Nrf2/MafG interaction.
  • Validation using cell-based reporter assays and in vitro biophysical methods to confirm inhibition of Nrf2/MafG heterodimerization.
  • Assessment of N1S effects on Nrf2-dependent gene expression and cisplatin sensitivity in cancer cells.

Main Results:

  • N1S effectively inhibits Nrf2/MafG heterodimerization in vitro and in cell-based assays.
  • Treatment with N1S leads to decreased transcription of Nrf2-dependent genes.
  • N1S sensitizes Nrf2-dependent cancer cells to cisplatin treatment, reducing their survival.

Conclusions:

  • N1S represents a novel, cell-permeable stapled peptide inhibitor of Nrf2/sMAF heterodimerization.
  • N1S demonstrates potential as a therapeutic agent to overcome chemoresistance in Nrf2-addicted cancers.
  • This approach offers a promising strategy for targeting transcription factor interactions in cancer therapy.

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