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Development of a Cell-Permeable Cyclic Peptidyl Inhibitor against the Keap1-Nrf2 Interaction.

ABSTRACT: Macrocyclic peptides have proven to be highly effective inhibitors of protein-protein interactions but generally lack cell permeability to access intracellular targets. We show herein that macrocyclic peptides may be rendered highly cell-permeable and biologically active by conjugating them with a cyclic cell-penetrating peptide (CPP). A previously reported cyclic peptidyl inhibitor against the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid-2 (Nrf2) interaction (K_D = 18 nM) was covalently attached to a cyclic CPP through a flexible linker. The resulting bicyclic peptide retained the Keap1-binding activity, resisted proteolytic degradation, readily entered mammalian cells, and activated the transcriptional activity of Nrf2 at nanomolar to low micromolar concentrations in cell culture. The inhibitor provides a useful tool for investigating the biological function of Keap1-Nrf2 and a potential lead for further development into a novel class of anti-inflammatory and anticancer agents. Our data suggest that other membrane-impermeable cyclic peptides may be similarly rendered cell-permeable by conjugation with a cyclic CPP.

SUBMITTER: Salim H

PROVIDER: S-EPMC7288753 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Development of a Cell-Permeable Cyclic Peptidyl Inhibitor against the Keap1-Nrf2 Interaction.

Salim Heba H Song Jian J Sahni Ashweta A Pei Dehua D

The Journal of organic chemistry 20191028 3

Macrocyclic peptides have proven to be highly effective inhibitors of protein-protein interactions but generally lack cell permeability to access intracellular targets. We show herein that macrocyclic peptides may be rendered highly cell-permeable and biologically active by conjugating them with a cyclic cell-penetrating peptide (CPP). A previously reported cyclic peptidyl inhibitor against the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid-2 (Nrf2) interaction (<i>K</i><su ...[more]

PMID: 31609620

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Project description:BackgroundNuclear factor erythroid-2 related factor 2 (NRF2) is a redox-sensitive transcription factor that positively regulates the expression of genes encoding antioxidants, xenobiotic detoxification enzymes, and drug efflux pumps, and confers cytoprotection against oxidative stress and xenobiotics in normal cells. Kelch-like ECH-associated protein 1 (KEAP1) negatively regulates NRF2 activity by targeting it to proteasomal degradation. Increased expression of cellular antioxidants and xenobiotic detoxification enzymes has been implicated in resistance of tumor cells against chemotherapeutic drugs.Methods and findingsHere we report a systematic analysis of the KEAP1 genomic locus in lung cancer patients and cell lines that revealed deletion, insertion, and missense mutations in functionally important domains of KEAP1 and a very high percentage of loss of heterozygosity at 19p13.2, suggesting that biallelic inactivation of KEAP1 in lung cancer is a common event. Sequencing of KEAP1 in 12 cell lines and 54 non-small-cell lung cancer (NSCLC) samples revealed somatic mutations in KEAP1 in a total of six cell lines and ten tumors at a frequency of 50% and 19%, respectively. All the mutations were within highly conserved amino acid residues located in the Kelch or intervening region domain of the KEAP1 protein, suggesting that these mutations would likely abolish KEAP1 repressor activity. Evaluation of loss of heterozygosity at 19p13.2 revealed allelic losses in 61% of the NSCLC cell lines and 41% of the tumor samples. Decreased KEAP1 activity in cancer cells induced greater nuclear accumulation of NRF2, causing enhanced transcriptional induction of antioxidants, xenobiotic metabolism enzymes, and drug efflux pumps.ConclusionsThis is the first study to our knowledge to demonstrate that biallelic inactivation of KEAP1 is a frequent genetic alteration in NSCLC. Loss of KEAP1 function leading to constitutive activation of NRF2-mediated gene expression in cancer suggests that tumor cells manipulate the NRF2 pathway for their survival against chemotherapeutic agents.

Dataset Information

Development of a Cell-Permeable Cyclic Peptidyl Inhibitor against the Keap1-Nrf2 Interaction.

Publications

Development of a Cell-Permeable Cyclic Peptidyl Inhibitor against the Keap1-Nrf2 Interaction.

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