TY - JOUR
T1 - Orally Bioavailable Prodrugs of ψ-GSH
T2 - A Potential Treatment for Alzheimer's Disease
AU - Xie, Wei
AU - Cao, Bin
AU - Zhu, Haizhou
AU - Raza, Abbas
AU - Juckel, Nicholas
AU - Xie, Jiashu
AU - Jiang, Rongrong
AU - Vince, Robert
AU - Lee, Michael K.
AU - More, Swati S.
N1 - Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.
PY - 2022/11/10
Y1 - 2022/11/10
N2 - Addressing glycation-induced oxidative stress in Alzheimer's disease (AD) is an emerging pharmacotherapeutic strategy. Restoration of the brain glyoxalase enzyme system that neutralizes reactive dicarbonyls is one such approach. Toward this end, we designed, synthesized, and evaluated a γ-glutamyl transpeptidase-resistant glyoxalase substrate, ψ-GSH. Although mechanistically successful, the oral efficacy of ψ-GSH appeared as an area in need of improvement. Herein, we describe our rationale for the creation of prodrugs that mask the labile sulfhydryl group. In vitro and in vivo stability studies identified promising prodrugs that could deliver pharmacologically relevant brain levels of ψ-GSH. When administered orally to a mouse model generated by the intracerebroventricular injection of Aβ1-42, the compounds conferred cognitive benefits. Biochemical and histological examination confirmed their effects on neuroinflammation and oxidative stress. Collectively, we have identified orally efficacious prodrugs of ψ-GSH that are able to restore brain glyoxalase activity and mitigate inflammatory and oxidative pathology associated with AD.
AB - Addressing glycation-induced oxidative stress in Alzheimer's disease (AD) is an emerging pharmacotherapeutic strategy. Restoration of the brain glyoxalase enzyme system that neutralizes reactive dicarbonyls is one such approach. Toward this end, we designed, synthesized, and evaluated a γ-glutamyl transpeptidase-resistant glyoxalase substrate, ψ-GSH. Although mechanistically successful, the oral efficacy of ψ-GSH appeared as an area in need of improvement. Herein, we describe our rationale for the creation of prodrugs that mask the labile sulfhydryl group. In vitro and in vivo stability studies identified promising prodrugs that could deliver pharmacologically relevant brain levels of ψ-GSH. When administered orally to a mouse model generated by the intracerebroventricular injection of Aβ1-42, the compounds conferred cognitive benefits. Biochemical and histological examination confirmed their effects on neuroinflammation and oxidative stress. Collectively, we have identified orally efficacious prodrugs of ψ-GSH that are able to restore brain glyoxalase activity and mitigate inflammatory and oxidative pathology associated with AD.
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U2 - 10.1021/acs.jmedchem.2c00779
DO - 10.1021/acs.jmedchem.2c00779
M3 - Article
C2 - 36353871
AN - SCOPUS:85140838679
SN - 0022-2623
VL - 65
SP - 14441
EP - 14455
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 21
ER -