Perfluoroarene-based peptide macrocycles that inhibit the Nrf2/Keap1 interaction

Bioorg Med Chem Lett. 2018 Sep 1;28(16):2728-2731. doi: 10.1016/j.bmcl.2018.03.003. Epub 2018 Mar 3.

Abstract

The Nrf2/Keap1 interaction is a target in the development of new therapeutic agents, where inhibition of the interaction activates Nrf2 and leads to the generation of downstream anti-inflammatory effects. Peptides that mimic the β-turn in the Keap1 active site and are constrained by a disulfide bridge have high affinity for Keap1 but no intracellular activity. The introduction of a perfluoroalkyl-bridging group to constrain the peptides, coupled with a glutamic acid to proline replacement leads to a new peptide with a Ki of 6.1 nM for the Nrf2/Keap1 binding interaction, although this does not translate into intracellular activity.

Keywords: Hexafluorobenzene; Keap1; Nrf2; Peptide; Protein-protein interaction.

MeSH terms

  • Dose-Response Relationship, Drug
  • Fluorocarbons / chemistry
  • Fluorocarbons / pharmacology*
  • Humans
  • Kelch-Like ECH-Associated Protein 1 / antagonists & inhibitors*
  • Kelch-Like ECH-Associated Protein 1 / metabolism
  • Macrocyclic Compounds / chemical synthesis
  • Macrocyclic Compounds / chemistry
  • Macrocyclic Compounds / pharmacology*
  • Molecular Structure
  • NF-E2-Related Factor 2 / antagonists & inhibitors*
  • NF-E2-Related Factor 2 / metabolism
  • Peptides / chemistry
  • Peptides / pharmacology*
  • Structure-Activity Relationship

Substances

  • Fluorocarbons
  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • Macrocyclic Compounds
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Peptides