Kelch-Like ECH-Associated Protein 1 (Keap1)/Nuclear Factor (Erythroid-Derived 2)-Like 2 (Nrf2)-Targeting Protein-Like Polymers Exhibit Prolonged Circulation Half-Lives and Nrf2 Pathway Activation In Vivo

Abstract Dysregulation of redox homeostasis underlies numerous acute and chronic pathologies, including neurodegenerative diseases and myocardial infarction (MI). Cellular defense against imposed oxidative stress is regulated by the intracellular protein–protein interaction (PPI) between Kelch-like ECH-associated protein 1 (Keap1) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Selective inhibition of the Keap1/Nrf2 interaction represents a promising therapeutic strategy to augment antioxidant defense in the context of oxidative stress. Recently, Keap1-inhibiting protein-like polymers (Keap1i-PLPs) were developed to selectively target the Keap1/Nrf2 PPI, activate antioxidant genes in primary cortical neuronal cultures, and promote a reparative response in vivo following MI. These results underscore the translational potential of Keap1i-PLPs. However, characterization of their in vivo pharmacokinetic and pharmacodynamic profiles remains essential prior to further clinical development. Herein, we describe these properties at three doses in healthy wild-type mice, in which prolonged circulation half-lives of 95 h were observed along with large volumes of distribution, primarily to clearance organs. Further, Nrf2 pathway activation was assessed in vivo in transgenic Nrf2 reporter mice, in which robust pathway activation was observed in the clearance organs of the liver and kidney as well as activation in the striatum and hippocampus of healthy mice.