Modified Peptide Inhibitors of the Keap1–Nrf2 Protein–Protein Interaction Incorporating Unnatural Amino Acids. (18th July 2018)

• Record Type: Journal Article
• Authors: Georgakopoulos, Nikolaos D.; Talapatra, Sandeep K.; Gatliff, Jemma; Kozielski, Frank; Wells, Geoff
• Is Part Of: Chembiochem. Volume 19:Number 17(2018)
• Page Start: 1810
• Page End: 1816
• Publication Date: 2018-07-18
• Subjects: Keap1 -- Nrf2 -- peptides -- protein–protein interactions -- unnatural amino acids; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201800170
• Languages: English
• ISSNs: 1439-4227

Abstract

Abstract: Noncovalent 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 in their promoter regions. Keap1 inhibitors based on peptide and small‐molecule templates have been identified. In this paper we develop the structure–activity relationships 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. Abstract : Increasing the activity : Peptide inhibitors of the Keap1–Nrf2 protein–protein interaction in which unnatural amino acids are incorporated in heptamer sequences have been developed. The starting sequence has been co‐crystallised with the Keap1 Kelch domain, and the best peptides have Keap1 affinities in the nanomolar range in fluorescence polarisation (FP) and isothermal titration calorimetry (ITC) binding assays.