Optimization of linear and cyclic peptide inhibitors of KEAP1-NRF2 protein-protein interaction

Bioorg Med Chem. 2020 Nov 1;28(21):115738. doi: 10.1016/j.bmc.2020.115738. Epub 2020 Aug 30.


Inhibition of KEAP1-NRF2 protein-protein interaction is considered a promising strategy to selectively and effectively activate NRF2, a transcription factor which is involved in several pathologies such as Huntington's disease (HD). A library of linear peptides based on the NRF2-binding motifs was generated on the nonapeptide lead Ac-LDEETGEFL-NH2 spanning residues 76-84 of the Neh2 domain of NRF2 with the aim to replace E78, E79 and E82 with non-acidic amino acids. A deeper understanding of the features and accessibility of the T80 subpocket was also targeted by structure-based design. Approaches to improve cell permeability were investigated using both different classes of cyclic peptides and conjugation to cell-penetrating peptides. This insight will guide future design of macrocycles, peptido-mimetics and, most importantly, small neutral brain-penetrating molecules to evaluate whether NRF2 activators have utility in HD.

Keywords: KEAP1/NRF2; PPI; Peptide Inhibitors.

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Cell Line, Tumor
  • Cell Membrane Permeability / drug effects
  • Drug Design
  • Humans
  • Kelch-Like ECH-Associated Protein 1 / antagonists & inhibitors
  • Kelch-Like ECH-Associated Protein 1 / metabolism*
  • Molecular Dynamics Simulation
  • NF-E2-Related Factor 2 / antagonists & inhibitors
  • NF-E2-Related Factor 2 / metabolism*
  • Peptides / chemistry*
  • Peptides / metabolism
  • Peptides / pharmacology
  • Peptides, Cyclic / chemistry*
  • Peptides, Cyclic / metabolism
  • Peptides, Cyclic / pharmacology
  • Protein Binding
  • Structure-Activity Relationship


  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • Peptides
  • Peptides, Cyclic