title: Peptide inhibitors of the Keap1-Nrf2 protein-protein interaction with improved binding and cellular activity.
abstract: Inhibitors of the Keap1-Nrf2 protein-protein interaction (PPI) have been proposed as potential anti-inflammatory and cancer chemopreventive agents. Such compounds have the potential to increase the intracellular concentrations of Nrf2 in a reversible manner and consequently increase the expression of a battery of gene products with antioxidant response elements (AREs) in their promoter region. In this manuscript we describe the development of peptide inhibitors with modified C- and N-termini and reduced overall charge. The activity of the compounds in inhibiting the PPI and in cellular assays of Nrf2 function are described. Compound 10 has potent activity (IC50 = 22 nM) in a cell-free fluorescence polarisation assay and induced the expression of Nrf2 dependent gene products in cells, suggesting that it has potential as a lead molecule for the development of peptidomimetic inhibitors.
authors.affiliation: UCL School of Pharmacy, University College London, London, United Kingdom.
authors.forename: Rowena
authors.initials: R
authors.lastname: Hancock
authors.forename: Marjolein
authors.initials: M
authors.lastname: Schaap
authors.forename: Helene
authors.initials: H
authors.lastname: Pfister
authors.forename: Geoff
authors.initials: G
authors.lastname: Wells
mesh_terms: D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D003124:Colorimetry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors*; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D051267:NF-E2-Related Factor 2; D010455:Peptides