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Issue 21, 2013
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Peptide inhibitors of the Keap1–Nrf2 proteinprotein interaction with improved binding and cellular activity

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Abstract

Inhibitors of the Keap1–Nrf2 proteinprotein interaction (PPI) have been proposed as potential anti-inflammatory and cancer chemopreventive agents. Such compounds have the potential to increase the intracellular concentrations of Nrf2 in a reversible manner and consequently increase the expression of a battery of gene products with antioxidant response elements (AREs) in their promoter region. In this manuscript we describe the development of peptide inhibitors with modified C- and N-termini and reduced overall charge. The activity of the compounds in inhibiting the PPI and in cellular assays of Nrf2 function are described. Compound 10 has potent activity (IC50 = 22 nM) in a cell-free fluorescence polarisation assay and induced the expression of Nrf2 dependent gene products in cells, suggesting that it has potential as a lead molecule for the development of peptidomimetic inhibitors.

Graphical abstract: Peptide inhibitors of the Keap1–Nrf2 protein–protein interaction with improved binding and cellular activity

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Publication details

The article was received on 03 Feb 2013, accepted on 12 Apr 2013 and first published on 16 Apr 2013


Article type: Paper
DOI: 10.1039/C3OB40249E
Citation: Org. Biomol. Chem., 2013,11, 3553-3557

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    Peptide inhibitors of the Keap1–Nrf2 proteinprotein interaction with improved binding and cellular activity

    R. Hancock, M. Schaap, H. Pfister and G. Wells, Org. Biomol. Chem., 2013, 11, 3553
    DOI: 10.1039/C3OB40249E

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