Raza Abbas, Xie Wei, Kim Kwan-Hyun, Dronamraju Venkateshwara Rao, Williams Jessica, Vince Robert, More Swati S
Center for Drug design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
Antioxidants (Basel). 2022 May 28;11(6):1075. doi: 10.3390/antiox11061075.
Supplementation of glutathione (GSH) levels through varying formulations or precursors has thus far appeared to be a tenable strategy to ameliorate disease-associated oxidative stress. Metabolic liability of GSH and its precursors, i.e., hydrolysis by the ubiquitous γ-glutamyl transpeptidase (γ-GT), has limited successful clinical translation due to poor bioavailability. We addressed this problem through the design of γ-GT-resistant GSH analogue, ψ-GSH, which successfully substituted in GSH-dependent enzymatic systems and also offered promise as a therapeutic for Alzheimer's disease (AD). With the aim to improve its bioavailability, we studied the utility of a ψ-GSH precursor, dipeptide , as a potential AD therapeutic. Compound retains the γ-GT stable ureide linkage and the thiol group for antioxidant property. By engaging glutathione synthetase, compound was able to generate ψ-GSH in vivo. It was found to be a modest cofactor of glutathione peroxidase and prevented cytotoxicity of Aβ-aggregates in vitro. Studies of compound in an acute AD model generated by intracerebroventricular injection of Aβ showed cognitive benefits, which were augmented by its combination with glycine along with mitigation of oxidative stress and inflammatory pathology. Collectively, these results support further optimization and evaluation of ψ-GSH dipeptide as a potential therapeutic in transgenic AD models.
迄今为止，通过不同配方或前体补充谷胱甘肽（GSH）水平似乎是减轻疾病相关氧化应激的一种可行策略。由于生物利用度差，GSH及其前体的代谢负担，即被普遍存在的γ-谷氨酰转肽酶（γ-GT）水解，限制了其在临床上的成功转化。我们通过设计抗γ-GT的GSH类似物ψ-GSH解决了这个问题，该类似物成功替代了GSH依赖性酶系统，并且有望成为治疗阿尔茨海默病（AD）的药物。为了提高其生物利用度，我们研究了ψ-GSH前体二肽作为潜在AD治疗药物的效用。化合物保留了γ-GT稳定的脲基连接和具有抗氧化特性的硫醇基团。通过参与谷胱甘肽合成酶，化合物能够在体内生成ψ-GSH。发现它是谷胱甘肽过氧化物酶的适度辅助因子，并在体外预防了Aβ聚集体的细胞毒性。在通过脑室内注射Aβ产生的急性AD模型中对化合物的研究显示出认知益处，与甘氨酸联合使用可增强这种益处，同时减轻氧化应激和炎症病理。总体而言，这些结果支持进一步优化和评估ψ-GSH二肽作为转基因AD模型中的潜在治疗药物。
