Neurodegeneration New Medicines Center and Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA; Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA, 92093, USA; Department of Neurology, Yale School of Medicine, New Haven, CT, 06510, USA.
Curr Opin Pharmacol. 2022 Oct;66:102267. doi: 10.1016/j.coph.2022.102267. Epub 2022 Jul 20.
Redox modifications are described that can be harnessed for the treatment of neurodegenerative disorders, including Alzheimer's disease (AD). The approach has shown potential therapeutic efficacy in AD in both transgenic mouse and hiPSC cerebral organoids models. In this review, two such redox targets are highlighted. First, protein S-nitrosylation of the NMDA-type of glutamate receptor is described as a potential therapeutic target. Second, an S-alkylation reaction of critical, redox-active cysteine thiol(s) on the protein KEAP1 to activate the anti-oxidant/anti-inflammatory transcription factor NRF2 is proposed. In both approaches, we utilize compounds described as pathologically activated therapeutics (or "PAT" drugs), which can only be activated by the disease process that they then combat. Thus, PAT drugs remain relatively innocuous and therefore clinically-tolerated in normal tissue in the absence of disease, thereby avoiding severe side effects both systemically and in the brain.
氧化还原修饰可被用于治疗神经退行性疾病，包括阿尔茨海默病（AD）。该方法在 AD 的转基因小鼠和 hiPSC 脑类器官模型中均显示出潜在的治疗效果。在本综述中，重点介绍了两种这样的氧化还原靶点。首先，描述了 NMDA 型谷氨酸受体的蛋白质 S-亚硝化为潜在的治疗靶点。其次，提出了在 KEAP1 蛋白上的关键氧化还原活性半胱氨酸巯基上的 S-烷基化反应，以激活抗氧化/抗炎转录因子 NRF2。在这两种方法中，我们利用了被描述为病理性激活治疗剂（或“PAT”药物）的化合物，这些化合物只能被它们所对抗的疾病过程激活。因此，PAT 药物在没有疾病的正常组织中相对无害，因此在系统和大脑中都避免了严重的副作用。
