Issue 21, 2013

Peptideinhibitors of the Keap1–Nrf2 protein–protein interaction with improved binding and cellular activity

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

Supplementary files

Article information

Article type
Paper
Submitted
03 feb 2013
Accepted
12 apr 2013
First published
16 apr 2013

Org. Biomol. Chem., 2013,11, 3553-3557

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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