Modified Peptide Inhibitors of the Keap1-Nrf2 Protein-Protein Interaction Incorporating Unnatural Amino Acids.
Nikolaos D GeorgakopoulosSandeep K TalapatraJemma GatliffFrank KozielskiGeoffrey WellsPublished in: Chembiochem : a European journal of chemical biology (2018)
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.
Keyphrases
- protein protein
- small molecule
- oxidative stress
- amino acid
- chronic obstructive pulmonary disease
- transcription factor
- gene expression
- poor prognosis
- high resolution
- dna methylation
- genome wide
- high throughput
- cognitive decline
- mass spectrometry
- heat shock
- mild cognitive impairment
- fluorescence imaging
- anti inflammatory
- living cells
- capillary electrophoresis
- fluorescent probe
- bioinformatics analysis