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. To study the acute effects of administering a Keap1i-PLP in a rat MI model, we induced a 35 minute ischemia reperfusion surgery in female Sprague Dawley rats. 1 day post surgery, n = 4-6 animals were injected with the following: saline, 3 mg/kg Keap1i-PLP, 7.5 mg/kg Keap1i-PLP, and scrambled 3mg/kg PLP.