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Peptide inhibitors of the Keap1-Nrf2 protein-protein interaction

Peptide inhibitors of the Keap1-Nrf2 protein-protein interaction

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Authors

  • Rowena Hancock
  • Helene C. Bertrand
  • Tadayuki Tsujita
  • Shama Naz
  • Ayman El-Bakry
  • Jitnueng Laoruchupong
  • John D. Hayes
  • Geoff Wells

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    Info

    Original languageEnglish
    Pages444-451
    Number of pages8
    JournalFree Radical Biology and Medicine
    Journal publication date15 Jan 2012
    Journal number2
    Volume52
    DOIs
    StatePublished

    Abstract

    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-a 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. (C) 2011 Elsevier Inc. All rights reserved.

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