Peptide inhibitors of the Keap1–Nrf2 protein–protein interaction

Hancock, R., Bertrand, H.C., Tsujita, T., Naz, S., El-Bakry, A., Laoruchupong, J., Hayes, J.D. and Wells, G. (2012) Peptide inhibitors of the Keap1–Nrf2 protein–protein interaction. Free Radical Biology and Medicine, 52 (2). pp. 444-451. 10.1016/j.freeradbiomed.2011.10.486.

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DOI: 10.1016/j.freeradbiomed.2011.10.486


Disruption of the interaction between the ubiquitination facilitator protein Keap1 and the cap'n'collar basic-region leucine-zipper transcription factor Nrf2 is a potential strategy to enhance expression of antioxidant and free radical detoxification gene products regulated by Nrf2. Agents that disrupt this protein-protein interaction may be useful pharmacological probes and future cancer-chemopreventive agents. We describe the structure-activity relationships for a series of peptides based upon regions of the Nrf2 Neh2 domain, of varying length and sequence, that interact with the Keap1 Kelch domain and disrupt the interaction with Nrf2. We have also investigated sequestosome-1 (p62) and prothymosin-α sequences that have been reported to interact with Keap1. To achieve this we have developed a high-throughput fluorescence polarization (FP) assay to screen inhibitors. In addition to screening synthetic peptides, we have used a phage display library approach to identify putative peptide ligands with non-native sequence motifs. Candidate peptides from the phage display library screening protocol were evaluated in the FP assay to quantify their binding activity. Hybrid peptides based upon the Nrf2 "ETGE" motif and the sequestosome-1 "Keap1-interaction region" have superior binding activity compared to either native peptide alone

Item Type:Article
Uncontrolled Keywords:Cancer chemoprevention; Compound screening; Fluorescence polarization; Free radicals; Keap1; Nrf2
Departments, units and centres:Department of Pharmaceutical and Biological Chemistry > Department of Pharmaceutical and Biological Chemistry
ID Code:3180
Journal or Publication Title:Free Radical Biology and Medicine
Deposited By:Library Staff
Deposited On:04 May 2012 16:50
Last Modified:04 May 2012 16:50


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