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

Bibliographische Detailangaben
Veröffentlicht in:	Advanced materials (Deerfield Beach, Fla.). - 1998. - 36(2024), 21 vom: 01. Mai, Seite e2311467
1. Verfasser:	Carrow, Kendal P (VerfasserIn)
Weitere Verfasser:	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:	Online-Aufsatz
Sprache:	English
Veröffentlicht:	2024
Zugriff auf das übergeordnete Werk:	Advanced materials (Deerfield Beach, Fla.)
Schlagworte:	Journal Article antioxidant biomaterial drug delivery peptides polymers Kelch-Like ECH-Associated Protein 1 NF-E2-Related Factor 2 Polymers KEAP1 protein, human Peptides

Beschreibung
Zusammenfassung:	© 2024 The Authors. Advanced Materials published by Wiley‐VCH GmbH. 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
Beschreibung:	Date Completed 24.05.2024 Date Revised 20.07.2024 published: Print-Electronic Citation Status MEDLINE
ISSN:	1521-4095
DOI:	10.1002/adma.202311467