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

Richard J. Steel, Maria A. O'Connell, Mark Searcey

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)
24 Downloads (Pure)

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 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.
Original languageEnglish
Pages (from-to)2728-2731
JournalBioorganic & Medicinal Chemistry Letters
Volume28
Issue number16
Early online date3 Mar 2018
DOIs
Publication statusPublished - 1 Sep 2018

Keywords

  • NRF2 or nuclear factor erythroid 2 [NF-E2]-related factor 2
  • Keap1
  • protein-protein interaction
  • hexafluorobenzene
  • peptide

Cite this