biostudies-literatureRaza ACenter for Drug Design, University of MinnesotaNIH HHS1075https://www.ebi.ac.uk/biostudies/studies/S-EPMC9219802biostudies-literatureUnknown11(6)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 <b>2</b>, as a potential AD therapeutic. Compound <b>2</b> retains the γ-GT stable ureide linkage and thAntioxidants (Basel, Switzerland)Dipeptide of ψ-GSH Inhibits Oxidative Stress and Neuroinflammation in an Alzheimer's Disease Mouse Model.PMC9219802NAR01AG062469Xie WMore SSWilliams JRaza AKim KHDronamraju VRVince RfalseDipeptide of ψ-GSH Inhibits Oxidative Stress and Neuroinflammation in an Alzheimer's Disease Mouse Model.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 <b>2</b>, as a potential AD therapeutic. Compound <b>2</b> retains the γ-GT stable ureide linkage and th2022-01-01T00:00:00Z2022 May2025-04-19T07:07:15.519Z2025-02-19T03:22:37.235ZS-EPMC92198023573997210.3390/antiox11061075