Protein‐Like Polymers Targeting Keap1/Nrf2 as Therapeutics for Myocardial Infarction
Abstract
Abstract 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 −1 , 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.
Article Details
Authors (18)
Joshua M. Mesfin
Kendal P. Carrow
Medical Scientist Training Program Department of Biomedical Engineering Northwestern University Feinberg School of Medicine Chicago IL 60611 USA
Alexander Chen
Madeline P. Hopps
Department of Chemistry International Institute for Nanotechnology Simpson‐Querrey Institute Chemistry of Life Processes Institute Northwestern University Evanston IL 60208 USA
JoJo J. Holm
Department of Chemistry International Institute for Nanotechnology Simpson‐Querrey Institute Chemistry of Life Processes Institute Northwestern University Evanston IL 60208 USA
Quincy P. Lyons
Shu Chien‐Gene Lay Department of Bioengineering Sanford Consortium for Regenerative Medicine University of California San Diego La Jolla CA 92037 USA
Michael B. Nguyen
Jervaughn D. Hunter
Assa Magassa
Department of Chemistry Department of Materials Science & Engineering Department of Pharmacology International Institute for Nanotechnology Simpson‐Querrey Institute Chemistry of Life Processes Institute Northwestern University Evanston IL 60208 USA
Elyse G. Wong
Kate Reimold
Shu Chien‐Gene Lay Department of Bioengineering Sanford Consortium for Regenerative Medicine University of California San Diego La Jolla CA 92037 USA
Sriya N. Paleti
Shu Chien‐Gene Lay Department of Bioengineering Sanford Consortium for Regenerative Medicine University of California San Diego La Jolla CA 92037 USA
Emily Gardner
Shu Chien‐Gene Lay Department of Bioengineering Sanford Consortium for Regenerative Medicine University of California San Diego La Jolla CA 92037 USA
Matthew P. Thompson
Pyrologix, Vibrant Planet
Colin G. Luo
Xiaoyu Zhang
Karen L. Christman
Nathan C. Gianneschi
Department of Materials Science & Engineering