Design and synthesis of Nrf2-derived hydrocarbon stapled peptides for the disruption of protein-DNA-interactions

PLoS One. 2022 Jun 22;17(6):e0267651. doi: 10.1371/journal.pone.0267651. eCollection 2022.

Abstract

Misregulation and mutations of the transcription factor Nrf2 are involved in the development of a variety of human diseases. In this study, we employed the technology of stapled peptides to address a protein-DNA-complex and designed a set of Nrf2-based derivatives. Varying the length and position of the hydrocarbon staple, we chose the best peptide for further evaluation in both fixed and living cells. Peptide 4 revealed significant enrichment within the nucleus compared to its linear counterpart 5, indicating potent binding to DNA. Our studies suggest that these molecules offer an interesting strategy to target activated Nrf2 in cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA
  • Humans
  • Hydrocarbons / chemistry
  • NF-E2-Related Factor 2* / genetics
  • Peptides* / chemistry

Substances

  • Hydrocarbons
  • NF-E2-Related Factor 2
  • Peptides
  • DNA

Grants and funding

This work was co funded by the German Federal ministry for Education and Research (NGFNPlus and e:Med) (Grant No. BMBF 01GS08104, 01ZX1303C), the Deutsche Forschungsgemeinschaft (DFG), the German federal state North Rhine Westphalia (NRW) and the European Union (European Regional Development Fund: Invest In Your Future) (EFRE-800400), NEGECA (PerMed NRW) and EMODI. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.