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The article discusses the protective effects of the proteostasis regulator compound AA147 against neurotoxic insults, particularly erastin-induced ferroptosis. It explains how AA147 activates the NRF2 oxidative stress response through metabolic activation by ER oxidases, targeting the NRF2 repressor protein KEAP1. The study explores modifying the amide linker of AA147 to enhance NRF2 activation and improve protection against neurotoxic insults. The findings suggest that replacing the amide linker with a carbamate linker retains NRF2 activation and enhances cellular tolerance and activity, paving the way for next-generation AA147 analogs with improved efficacy in disease-relevant assays.
We previously showed that the proteostasis regulator compound AA147 (N-(2-hydroxy-5-methylphenyl)benzenepropanamide) potently protects against neurotoxic insults, such as glutamate-induced oxytosis. Though AA147 is a selective activator of the ATF6 arm of the unfolded protein response in non-neuronal cells, AA147-dependent protection against glutamate toxicity in cells of neuronal origin is primarily mediated through activation of the NRF2 oxidative stress response. AA147 activates NRF2 through a mechanism involving metabolic activation of AA147 by endoplasmic reticulum (ER) oxidases, affording an AA147-based quinone methide that covalently targets the NRF2 repressor protein KEAP1. Previous results show that the 2-amino-p-cresol A-ring of AA147 is required for NRF2 activation, while the phenyl B-ring of AA147 is amenable to modification. Here we explore whether the protease-sensitive amide linker between the A- and B-rings of this molecule can be modified to retain NRF2 activation. We show that replacement of the amide linker of AA147 with a carbamate linker retains NRF2 activation in neuronal cells and improves protection against neurotoxic insults, including glutamate-induced oxytosis and erastin-induced ferroptosis. Moreover, we demonstrate that inclusion of this carbamate linker facilitates identification of next-generation AA147 analogs with improved cellular tolerance and activity in disease-relevant assays.
This article is Open Access
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