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journal article·2024-05Open access

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

Kendal P. Carrow, Haylee L. Hamilton, Madeline P. Hopps, Yang Li, Baofu Qiao, N. Connor Payne, Matthew P. Thompson, Xiaoyu Zhang, Assa Magassa, Mara Fattah, Shivangi Agarwal, Michael P. Vincent, Marina Buyanova, Paul A. Bertin, Ralph Mazitschek, Monica Olvera de la Cruz, Delinda A. Johnson, Jeffrey A. Johnson, Nathan C. Gianneschi

Advanced Materials· Volume 36· Issue 21
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Source abstract

Abstract

Abstract 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.
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Research context

Polymers

OpenAlex topics: Genomics, phytochemicals, and oxidative stress · Fungal and yeast genetics research · Endoplasmic Reticulum Stress and Disease

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Biomedical Engineering McCormick School of Engineering Medical Scientist Training Program Feinberg School of Medicine International Institute for Nanotechnology Northwestern University Evanston 60208 IL USA

School of Pharmacy University of Wisconsin Madison 57305 WI USA

International Institute for Nanotechnology Department of Chemistry Chemistry of Life Processes Institute Northwestern University Evanston 60208 IL USA

Department of Chemical and Biological Engineering McCormick School of Engineering, Northwestern University Evanston 60208 IL USA

Department of Natural Sciences Baruch College City University of New York New York 10010 NY USA

Center for Systems Biology Massachusetts General Hospital Harvard Medical School Boston MA USA

Department of Chemistry & Chemical Biology Harvard University Cambridge 02138 MA USA

Grove Biopharma Inc 1375 W. Fulton St., Ste. 650 Chicago 60558 IL USA

Broad Institute of MIT and Harvard Cambridge 02142 MA USA

Harvard T.H. Chan School of Public Health Boston 02115 MA USA

Department of Materials Science & Engineering Robert R. McCormick School of Engineering and Applied Science Center for Computation and Theory of Soft Materials Northwestern University Evanston 60208 IL USA

Departments of Chemistry Materials Science & Engineering Biomedical Engineering Pharmacology Simpson Querrey Institute Chemistry of Life Processes Institute Lurie Cancer Center International Institute for Nanotechnology Northwestern University Evanston 60208 IL USA

Funding

Damon Runyon Cancer Research Foundation · National Institutes of Health · National Institute on Aging · National Science Foundation · National Cancer Institute · International Institute for Nanotechnology, Northwestern University

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