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Kendal P Carrow1, Haylee L Hamilton2, Madeline P Hopps3

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New polymer-based proteomimetics selectively inhibit the Keap1/Nrf2 interaction, enhancing the antioxidant response. This approach overcomes limitations of small molecules and peptides, offering potential therapeutic benefits for neurodegenerative diseases.

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Area of Science:

  • Biochemistry
  • Polymer Chemistry
  • Neuroscience

Background:

  • Inhibition of the nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associating protein 1 (Keap1) protein-protein interaction (PPI) enhances antioxidant response.
  • Small molecules and peptides face challenges like off-target effects, poor cellular permeability, degradation, and limited penetration.

Purpose of the Study:

  • To develop a novel polymer-based proteomimetic strategy to overcome the limitations of existing Nrf2-Keap1 inhibitors.
  • To create a system that selectively inhibits Keap1/Nrf2 interaction, enhances cellular antioxidant response, and demonstrates therapeutic potential for neurodegenerative diseases.

Main Methods:

  • Synthesized protein-like polymers (PLPs) with a lipophilic backbone displaying Keap1-binding peptides in a brush architecture.
  • Evaluated PLP's ability to engage Keap1, displace Nrf2, and activate the antioxidant response element (ARE) pathway in cellular models, including primary cortical neurons.

Main Results:

  • PLPs demonstrated significantly increased Keap1 binding affinity compared to free peptides.
  • PLPs exhibited enhanced serum stability and cell penetration capabilities.
  • Selective activation of the ARE pathway was observed in cellular assays, including primary neuronal cultures.

Conclusions:

  • Polymer-based proteomimetics effectively overcome barriers associated with peptide and small molecule inhibitors for targeting the Keap1/Nrf2 pathway.
  • These novel PLPs show promise for treating diseases linked to oxidative stress, such as neurodegenerative disorders.