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

• Published in: Bioorganic & medicinal chemistry letters Vol. 28; no. 16; pp. 2728 - 2731
• Main Authors: Steel, Richard J., O'Connell, Maria A., Searcey, Mark
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.09.2018; Elsevier
• Subjects: Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; Fluorocarbons - chemistry; Fluorocarbons - pharmacology; Hexafluorobenzene; Humans; Keap1; Kelch-Like ECH-Associated Protein 1 - antagonists & inhibitors; Kelch-Like ECH-Associated Protein 1 - metabolism; Life Sciences & Biomedicine; 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; Nrf2; Peptide; Peptides - chemistry; Peptides - pharmacology; Pharmacology & Pharmacy; Physical Sciences; Protein-protein interaction; Science & Technology; Structure-Activity Relationship; Keap1; Hexafluorobenzene; Protein-protein interaction; Nrf2; Peptide; KEAP1-NRF2 INTERACTION; DISCOVERY; GENE; INTERFACE; PATHWAY; UPDATE; PROVIDES; BINDING
• DOI: 10.1016/j.bmcl.2018.03.003
• ISSN: 0960-894X; 1464-3405

[Display omitted] 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.