Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.
ACS Chem Neurosci. 2012 Mar 21;3(3):204-10. doi: 10.1021/cn200113z. Epub 2012 Jan 3.
The antioxidant properties of glutathione (GSH) and their relevance to oxidative stress induced pathological states such as Alzheimer's disease is well-established. The utility of GSH itself as a pharmacotherapeutic agent for such disorders is limited because of the former's lability to breakdown through amide cleavage by the ubiquitous enzyme γ-glutamyl transpeptidase (γ-GT). In the present study, a GSH analogue, Ψ-GSH, where the γ-glutamylcysteine amide linkage is replaced with a ureide linkage, was synthesized. Ψ-GSH was found to be stable toward γ-GT mediated breakdown. Ψ-GSH fulfilled four cardinal properties of GSH, namely, traversing across the blood brain barrier (BBB) via the GSH active uptake machinery, replacing GSH in the glyoxalase-I mediated detoxification of methylglyoxal, protecting cells against chemical oxidative insult, and finally lowering the cytotoxicity of amyloid-β peptide. These results validate Ψ-GSH as a viable metabolically stable replacement for GSH and establish it as a potential preclinical candidate for treatment of oxidative stress mediated pathology.
谷胱甘肽 (GSH) 的抗氧化特性及其与阿尔茨海默病等氧化应激诱导的病理状态的相关性已得到充分证实。由于 GSH 本身容易通过普遍存在的酶 γ-谷氨酰转肽酶 (γ-GT) 通过酰胺裂解分解，因此其作为此类疾病的药物治疗剂的用途有限。在本研究中，合成了一种 GSH 类似物 Ψ-GSH，其中 γ-谷氨酰半胱氨酸酰胺键被脲键取代。发现 Ψ-GSH 对 γ-GT 介导的分解稳定。Ψ-GSH 具有 GSH 的四个主要特性，即通过 GSH 主动摄取机制穿过血脑屏障 (BBB)、在甘油醛-1 介导的甲基乙二醛解毒中替代 GSH、保护细胞免受化学氧化损伤，最后降低淀粉样β肽的细胞毒性。这些结果验证了 Ψ-GSH 作为 GSH 的可行代谢稳定替代品，并将其确立为治疗氧化应激介导的病理学的潜在临床前候选药物。
