2025/04/25 by Joshua M. Mesfin, Kendal P. Carrow, Alexander Chen +15 · 1 voice · 7 citations
Biochemistry, Genetics and Molecular Biology · Chemistry · Medicine · #Biochemistry #Biology #Cardiac Fibrosis and Remodeling #Cardiovascular Function and Risk Factors #Cell biology #Chemistry #Cytoprotection #Genomics, phytochemicals, and oxidative stress #Heart failure #In vitro #In vivo #Internal medicine #Intracellular #KEAP1 #Medicine #Myocardial infarction #Oxidative stress #Pharmacology
paper · pdf · doi:10.1002/adma.202417885
published in Advanced Materials 37(27), e2417885
openalex publication_date 2025/04/25 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/06
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.