Protein‐Like Polymers Targeting Keap1/Nrf2 as Therapeutics for Myocardial Infarction
Myocardial infarction (MI) results in oxidative stress to the myocardium and frequently leads to heart failure (HF). There is an unmet clinical need to develop therapeutics that address the inflammatory stress response and prevent negative left ventricular remodeling. Here, the Keap1/Nrf2 protein-protein interaction is specifically targeted, as Nrf2 activation is known to mitigate the inflammatory response following MI. This is achieved using a Nrf2-mimetic protein-like polymer (PLP) to inhibit the Keap1-Nrf2 interaction. The PLP platform technology provides stability in vivo, potent intracellular bioactivity, and multivalency leading to high avidity Keap1 binding. In vitro and in vivo assays to probe cellular activity and MI therapeutic utility are employed. These Keap1-inhibiting PLPs (Keap1i-PLPs) impart cytoprotection from oxidative stress via Nrf2 activation at sub-nanomolar concentrations in primary cardiomyocytes. Single-digit mg kg<sup>-1</sup>, single-dose, intravenous PLP administration significantly improves cardiac function in rats post-MI through immunomodulatory, anti-apoptotic, and angiogenic mechanisms. Thus Keap1i-PLPs disrupt key intracellular protein-protein interactions following intravenous, systemic administration in vivo. These results have broad implications not only for MI but also for other oxidative stress-driven diseases and conditions.
Authors
- Jürgen Holm
- Matthew P. Thompson (ORCID: https://orcid.org/0000-0002-0428-291X)
- Karen L. Christman (ORCID: https://orcid.org/0000-0002-6179-898X)
- Emily Gardner (ORCID: https://orcid.org/0000-0002-1265-2298)
- Michael Nguyen (ORCID: https://orcid.org/0000-0003-1847-4557)
- Jervaughn D. Hunter (ORCID: https://orcid.org/0000-0001-9374-5420)
- Nathan C. Gianneschi (ORCID: https://orcid.org/0000-0001-9945-5475)
- Joshua M. Mesfin (ORCID: https://orcid.org/0000-0003-1022-8175)
- Kendal P. Carrow (ORCID: https://orcid.org/0000-0002-3996-3352)
- Colin Luo (ORCID: https://orcid.org/0000-0002-3269-2027)
- Alexander Chen (ORCID: https://orcid.org/0000-0002-8396-8759)
- Assa Magassa (ORCID: https://orcid.org/0000-0001-6082-0324)
- Madeline P. Hopps (ORCID: https://orcid.org/0000-0002-0531-8582)
- Kate E. Reimold (ORCID: https://orcid.org/0009-0006-5353-4614)
- Xiaoyu Zhang (ORCID: https://orcid.org/0000-0002-0951-9664)
- Elizabeth Wong
- Sriya N. Paleti
- Quincy P. Lyons (ORCID: https://orcid.org/0009-0003-1042-5627)
Institutions
- Northwestern University (US)
- University of California San Diego (US)
- Sanford Consortium for Regenerative Medicine (US)
- International Institute for Nanotechnology
Publication Details
- Journal
- Advanced Materials
- Published
- 2025-04-25
- DOI
- https://doi.org/10.1002/adma.202417885
- Citations
- 5
- Primary Topic
- Genomics, phytochemicals, and oxidative stress
- Type
- article
- Field-Weighted Citation Impact
- 4.03
Funders
- American Heart Association
- Damon Runyon Cancer Research Foundation
- National Institutes of Health
- Robert H. Lurie Comprehensive Cancer Center
- National Institute on Aging
- National Heart, Lung, and Blood Institute
- National Institute of Biomedical Imaging and Bioengineering
- Basic Research Laboratory