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Peptide and small molecule inhibitors of the Keap1-Nrf2 protein-protein interaction

Geoff Wells1

  • 1UCL School of Pharmacy, 29/39 Brunswick Square, University College London, London, WC1N 1AX, U.K. g.wells@ucl.ac.uk.

Biochemical Society Transactions
|November 10, 2015
PubMed

Insights

Nuclear factor erythroid-2-related factor 2 (Nrf2) protects cells from oxidative damage. This review covers protein-protein interaction inhibitors that modulate Nrf2 activity for therapeutic benefits.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor that up-regulates cytoprotective enzymes, offering protection against oxidative damage.
  • Increasing Nrf2 activity is a therapeutic strategy for neurodegenerative diseases and cancer chemoprevention.
  • Nrf2 activity is negatively regulated by Kelch-like ECH-associated protein 1 (Keap1), which targets Nrf2 for degradation.

Purpose of the Study:

  • To review various classes of protein-protein interaction (PPI) inhibitors targeting the Keap1-Nrf2 interaction.
  • To discuss the molecular mechanisms and biological activities of these inhibitors.
  • To highlight emerging evidence on the similarities and differences in their biological effects.

Main Methods:

  • Literature review of published studies on Keap1-Nrf2 PPI inhibitors.
  • Analysis of molecular mechanisms of action for different inhibitor classes (e.g., covalent modifiers, small molecule inhibitors, peptides).
  • Evaluation of biological activities and therapeutic potential reported in preclinical studies.

Main Results:

  • Nrf2 activity can be modulated by inhibiting the Keap1-Nrf2 interaction.
  • Natural products like sulforaphane and synthetic compounds (peptides, small molecules) target this interaction.
  • Inhibitors exhibit distinct molecular interactions with Keap1, leading to varied biological outcomes.

Conclusions:

  • Inhibition of the Keap1-Nrf2 interaction is a promising therapeutic approach.
  • Different classes of PPI inhibitors offer diverse strategies for modulating Nrf2 activity.
  • Further research is needed to elucidate the full therapeutic potential and comparative efficacy of these compounds.
Keywords:
Kelch-like ECH-associated protein 1 (Keap1)drug discoverynuclear factor erytheroid-2-related factor 2 (Nrf2)protein–protein interactions

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