Metabolically activated proteostasis regulators that protect against erastin-induced ferroptosis†

IF 4.2 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Gabriel M. Kline, Nicole Madrazo, Christian M. Cole, Meera Pannikkat, Michael J. Bollong, Jessica D. Rosarda, Jeffery W. Kelly and R. Luke Wiseman
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Abstract

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.

Abstract Image

Abstract Image

新陈代谢激活的蛋白稳态调节因子可抵御麦拉宁诱导的铁蛋白沉积症
我们之前研究发现,蛋白稳态调节剂化合物AA147(N-(2-羟基-5-甲基苯基)苯丙酰胺)能有效防止神经毒性损伤,如谷氨酸诱导的氧中毒。尽管 AA147 在非神经元细胞中是未折叠蛋白反应的 ATF6 部分的选择性激活剂,但在神经元细胞中,AA147 依赖性的谷氨酸毒性保护主要是通过激活 NRF2 氧化应激反应介导的。AA147 激活 NRF2 的机制涉及内质网(ER)氧化酶对 AA147 的代谢活化,从而产生一种以 AA147 为基础的醌甲酰胺,它能共价地靶向 NRF2 抑制蛋白 KEAP1。之前的研究结果表明,AA147 的 2-amino-p-cresol A 环是 NRF2 激活所必需的,而 AA147 的苯基 B 环则可进行修饰。在此,我们探讨了能否对该分子的 A 环和 B 环之间对蛋白酶敏感的酰胺连接物进行修饰,以保留 NRF2 的激活作用。我们的研究表明,用氨基甲酸酯连接体取代 AA147 的酰胺连接体可保留神经元细胞中 NRF2 的活化,并改善对神经毒性损伤的保护,包括谷氨酸诱导的氧中毒和麦拉宁诱导的铁中毒。此外,我们还证明,加入这种氨基甲酸酯连接物有助于鉴定下一代 AA147 类似物,它们在疾病相关的实验中具有更好的细胞耐受性和活性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
6.10
自引率
0.00%
发文量
128
审稿时长
10 weeks
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