Peptide inhibitors of the Keap1-Nrf2 protein-protein interaction

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

    Research output: Contribution to journalArticle

    68 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)444-451
    Number of pages8
    JournalFree Radical Biology and Medicine
    Volume52
    Issue number2
    DOIs
    Publication statusPublished - 15 Jan 2012

    Keywords

    • Fluorescence polarization
    • Cancer chemoprevention
    • Compound screening
    • Nrf2
    • Keap1
    • Free radicals
    • TRANSCRIPTION FACTOR NRF2
    • OXIDATIVE STRESS
    • PROTEASOMAL DEGRADATION
    • GENE-EXPRESSION
    • DLG MOTIFS
    • ACTIVATION
    • MECHANISM
    • PATHWAY
    • CANCER
    • UBIQUITINATION

    Cite this

    Hancock, R., Bertrand, H. C., Tsujita, T., Naz, S., El-Bakry, A., Laoruchupong, J., ... Wells, G. (2012). Peptide inhibitors of the Keap1-Nrf2 protein-protein interaction. Free Radical Biology and Medicine, 52(2), 444-451. https://doi.org/10.1016/j.freeradbiomed.2011.10.486
    Hancock, Rowena ; Bertrand, Helene C. ; Tsujita, Tadayuki ; Naz, Shama ; El-Bakry, Ayman ; Laoruchupong, Jitnueng ; Hayes, John D. ; Wells, Geoff. / Peptide inhibitors of the Keap1-Nrf2 protein-protein interaction. In: Free Radical Biology and Medicine. 2012 ; Vol. 52, No. 2. pp. 444-451.
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    Hancock, R, Bertrand, HC, Tsujita, T, Naz, S, El-Bakry, A, Laoruchupong, J, Hayes, JD & Wells, G 2012, 'Peptide inhibitors of the Keap1-Nrf2 protein-protein interaction', Free Radical Biology and Medicine, vol. 52, no. 2, pp. 444-451. https://doi.org/10.1016/j.freeradbiomed.2011.10.486

    Peptide inhibitors of the Keap1-Nrf2 protein-protein interaction. / Hancock, Rowena; Bertrand, Helene C.; Tsujita, Tadayuki; Naz, Shama; El-Bakry, Ayman; Laoruchupong, Jitnueng; Hayes, John D.; Wells, Geoff.

    In: Free Radical Biology and Medicine, Vol. 52, No. 2, 15.01.2012, p. 444-451.

    Research output: Contribution to journalArticle

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    AU - Hancock, Rowena

    AU - Bertrand, Helene C.

    AU - Tsujita, Tadayuki

    AU - Naz, Shama

    AU - El-Bakry, Ayman

    AU - Laoruchupong, Jitnueng

    AU - Hayes, John D.

    AU - Wells, Geoff

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    KW - Cancer chemoprevention

    KW - Compound screening

    KW - Nrf2

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    KW - Free radicals

    KW - TRANSCRIPTION FACTOR NRF2

    KW - OXIDATIVE STRESS

    KW - PROTEASOMAL DEGRADATION

    KW - GENE-EXPRESSION

    KW - DLG MOTIFS

    KW - ACTIVATION

    KW - MECHANISM

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    KW - CANCER

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    Hancock R, Bertrand HC, Tsujita T, Naz S, El-Bakry A, Laoruchupong J et al. Peptide inhibitors of the Keap1-Nrf2 protein-protein interaction. Free Radical Biology and Medicine. 2012 Jan 15;52(2):444-451. https://doi.org/10.1016/j.freeradbiomed.2011.10.486