Georgakopoulos, N;
Talapatra, S;
Gatliff, J;
Kozielski, F;
Wells, G;
(2018)
Modified peptide inhibitors of the Keap1-Nrf2 protein-protein interaction incorporating unnatural amino acids.
ChemBioChem
10.1002/cbic.201800170.
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | Modified peptide inhibitors of the Keap1-Nrf2 protein-protein interaction incorporating unnatural amino acids |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/cbic.201800170 |
| Publisher version: | https://doi.org/10.1002/cbic.201800170 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| Keywords: | Keap1, Nrf2, Protein-protein interaction, crystallography, peptides |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10051120 |
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