Stapled Peptides as Direct Inhibitors of Nrf2-sMAF Transcription Factors

Ramya Modi, Nick McKee, Ning Zhang, Amir Alwali, Samantha Nelson, Aditi Lohar, Raluca Ostafe, Donna D. Zhang, Elizabeth I. Parkinson

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Nuclear factor erythroid-related 2-factor 2 (Nrf2) is a transcription factor traditionally thought of as a cellular protector. However, in many cancers, Nrf2 is constitutively activated and correlated with therapeutic resistance. Nrf2 heterodimerizes with small musculoaponeurotic fibrosarcoma Maf (sMAF) transcription factors, allowing binding to the antioxidant responsive element (ARE) and induction of transcription of Nrf2 target genes. While transcription factors are historically challenging to target, stapled peptides have shown great promise for inhibiting these protein-protein interactions. Herein, we describe the first direct cell-permeable inhibitor of Nrf2/sMAF heterodimerization. N1S is a stapled peptide designed based on AlphaFold predictions of the interactions between Nrf2 and sMAF MafG. A cell-based reporter assay combined with in vitro biophysical assays demonstrates that N1S directly inhibits Nrf2/MafG heterodimerization. N1S treatment decreases the transcription of Nrf2-dependent genes and sensitizes Nrf2-dependent cancer cells to cisplatin. Overall, N1S is a promising lead for the sensitization of Nrf2-addicted cancers.

Original languageEnglish (US)
Pages (from-to)6184-6192
Number of pages9
JournalJournal of Medicinal Chemistry
Issue number9
StatePublished - May 11 2023

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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