Modified Peptide Inhibitors of the Keap1-Nrf2 Protein-Protein Interaction Incorporating Unnatural Amino Acids.

Non‐covalent inhibitors of the Keap1‐Nrf2 protein‐protein interaction (PPI) have therapeutic potential in a range of disease states including neurodegenerative diseases (Parkinson's and Alzheimer's diseases), chronic obstructive pulmonary disease and various inflammatory conditions. By stalling Keap1‐mediated ubiquitination of Nrf2, such compounds can enhance Nrf2 transcriptional activity and activate the expression of a range of genes with antioxidant response elements (AREs) in their promoter regions. Keap1 inhibitors have been identified based on peptide and small molecule templates. In this paper we develop the SAR of the peptide series and identify a group of ligands incorporating unnatural amino acids that demonstrate improved binding affinity in fluorescence polarisation, differential scanning fluorimetry and isothermal titration calorimetry assays. These modified peptides have the potential for further development into peptidomimetic chemical probes to explore the role of Nrf2 in disease and as potential lead structures for drug development.