Inhibiting the Keap1/Nrf2 Protein‐Protein Interaction with Protein‐Like Polymers

• Published in: Advanced materials (Weinheim) Vol. 36; no. 21; pp. e2311467 - n/a
• Main Authors: Carrow, Kendal P., Hamilton, Haylee L., Hopps, Madeline P., Li, Yang, Qiao, Baofu, Payne, N. Connor, Thompson, Matthew P., Zhang, Xiaoyu, Magassa, Assa, Fattah, Mara, Agarwal, Shivangi, Vincent, Michael P., Buyanova, Marina, Bertin, Paul A., Mazitschek, Ralph, Olvera de la Cruz, Monica, Johnson, Delinda A., Johnson, Jeffrey A., Gianneschi, Nathan C.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01-05-2024
• Subjects: antioxidant; Antioxidants; Binding; biomaterial; drug delivery; Peptides; Polymers; Proteins; peptides; antioxidant; drug delivery; polymers; biomaterial
• ISSN: 0935-9648; 1521-4095; 1521-4095
• DOI: 10.1002/adma.202311467

Successful and selective inhibition of the cytosolic protein‐protein interaction (PPI) between nuclear factor erythroid 2‐related factor 2 (Nrf2) and Kelch‐like ECH‐associating protein 1 (Keap1) can enhance the antioxidant response, with the potential for a therapeutic effect in a range of settings including in neurodegenerative disease (ND). Small molecule inhibitors have been developed, yet many have off‐target effects, or are otherwise limited by poor cellular permeability. Peptide‐based strategies have also been attempted to enhance specificity, yet face challenges due to susceptibility to degradation and lack of cellular penetration. Herein, these barriers are overcome utilizing a polymer‐based proteomimetics. The protein‐like polymer (PLP) consists of a synthetic, lipophilic polymer backbone displaying water soluble Keap1‐binding peptides on each monomer unit forming a brush polymer architecture. The PLPs are capable of engaging Keap1 and displacing the cellular protective transcription factor Nrf2, which then translocates to the nucleus, activating the antioxidant response element (ARE). PLPs exhibit increased Keap1 binding affinity by several orders of magnitude compared to free peptides, maintain serum stability, are cell‐penetrant, and selectively activate the ARE pathway in cells, including in primary cortical neuronal cultures. Keap1/Nrf2‐inhibitory PLPs have the potential to impact the treatment of disease states associated with dysregulation of oxidative stress, such as NDs.
The protein‐protein interaction between Kelch‐like ECH associating protein 1 (Keap1) and nuclear factor erthroid 2‐related factor 2 (Nrf2) regulates the antioxidant response. Protein‐like polymers (PLPs) were developed to inhibit the Keap1/Nrf2 PPI as multivalent, stable, and bioactive compounds. The polymers overcome prior limitations and serve as both a chemical biology tool and foundation for Keap1/Nrf2 targeted therapeutics.