Orally Bioavailable Prodrugs of ψ-GSH: A Potential Treatment for Alzheimer's Disease

Wei Xie, Bin Cao, Haizhou Zhu, Abbas Raza, Nicholas Juckel, Jiashu Xie, Rongrong Jiang, Robert Vince, Michael K. Lee, Swati S. More

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)14441-14455
Number of pages15
JournalJournal of medicinal chemistry
Volume65
Issue number21
DOIs
StatePublished - Nov 10 2022

Bibliographical note

Funding Information:
This research was funded by National Institutes of Health Grants to S.S.M. (R01-AG062469, 1912-37730A) and M.K.L. (RF1-AG062135, R01-NS108686, 1902-36759A) and by funding from the Center for Drug Design (CDD), University of Minnesota.

Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

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