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2000
Volume 25, Issue 11
  • ISSN: 1389-5575
  • E-ISSN: 1875-5607

Abstract

O-GlcNAcylation is a non-canonical form of protein glycosylation that occurs in nuclear, cytoplasmic, and mitochondrial proteins among all multicellular eukaryotes. There are only two enzymes that regulate this post-translational modification, one of which is O-GlcNAcase, a glycoside hydrolase that catalyzes the hydrolytic cleavage of O-GlcNAc from protein substrates. Related studies have shown that the reduction of O-GlcNAc levels is closely related to Alzheimer's disease, which is maintained by reducing the aggregation of tau inhibiting O-GlcNAcase. Various small-molecule O-GlcNAcase inhibitors with different chemical structures have been developed and used as chemical probes to explore the O-GlcNAc pathway. Although many reported inhibitors have shown that O-GlcNAcase activity has single-digit nmol IC values in binding assays, and molecules, such as LY-3372689, have entered phase II clinical studies, further exploration of novel O-GlcNAcase inhibitors with higher inhibitory activity and specificity is still worthy of attention. This article reviews the pathogenesis and therapeutic role of O-GlcNAcase in Alzheimer's disease, as well as the recent progress of O-GlcNAcase small molecule inhibitors, including sugar-derived or non-sugar scaffolds, and summarizes the clinical progress and potential prospects of O-GlcNAcase inhibitors.

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/content/journals/mrmc/10.2174/0113895575376839250606183944
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Recent Progress of Small-molecule Inhibitors of O-GlcNAcase for Alzheimer’s Disease
Mini Rev Med Chem 25, 821 (2025); https://doi.org/10.2174/0113895575376839250606183944
/content/journals/mrmc/10.2174/0113895575376839250606183944
/content/journals/mrmc/10.2174/0113895575376839250606183944
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  • Article Type:     Review Article
Keyword(s): Alzheimer's disease; nonsugar inhibitors; OGA; small molecule; sugar-derived inhibitors; tau

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