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 a need to therapeutically treat the inflammatory stress response and thus prevent negative left ventricular remodeling. Thus, we specifically target the protein-protein interaction between Nrf2 and Keap1, as Nrf2 activation is known to mitigate MI. We further leverage Nrf2 activation using a proteomimetic platform to inhibit the Keap1-Nrf2 axis via protein-like polymers (PLPs), given its stability in vivo, prolonged circulatory half-life, potent intracellular bioactivity, and multivalency. We employed in vitro and in vivo assays to probe cellular activity and MI therapeutic utility. These Keap1-inhibiting PLPs (Keap1i-PLPs) exhibit primary cardiomyocyte cytoprotection from oxidative stress via Nrf2 activation at sub-nanomolar concentrations. Single-digit mg/kg, single-dose, intravenous PLP treatment significantly improves cardiac function in rats post-MI through immunomodulatory, anti-apoptotic, and angiogenic mechanisms. Thus Keap1i-PLPs disrupt key intracellular PPIs following intravenous, systemic administration in vivo. These results have broad implications not only for MI, but also for other oxidative stress diseases.