Oct 2026· Current Opinion in Chemical Biology· Vol 95, pp.
102785
· 0 citations· 48 references
Medicine
Abstract
O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) is an essential and dynamic post-translational modification (PTM) that modulates diverse cellular processes. Dysregulation of O-GlcNAcylation is associated with numerous human diseases, yet no O-GlcNAc-targeting therapy has been approved for clinical use, underscoring the need for tools that enable precise functional dissection of this modification. In this review, we survey emerging chemical strategies over the past two years that extend beyond conventional active-site inhibition, covering both chemically induced proximity (CIP) platforms for substrate-specific O-GlcNAc editing and non-canonical global modulators including allosteric ligands and splicing modulators. We discuss the design principles of these emerging tools, their applications in functional studies, and their current limitations. The continued evolution of these chemical approaches will accelerate the functional annotation of the O-GlcNAcome and may ultimately inform therapeutic strategies targeting O-GlcNAc dysregulation.
O-linked N-acetylglucosamine glycosylation (O-GlcNAcylation) regulates many intracellular proteins, but linking a cellular phenotype to O-GlcNAcylation of a specific substrate remains difficult. Global perturbation of O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA) changes many proteins at once and therefore provides l...
Tong-Yang Xu, Billy Wai-Lung Ng· Glycobiology· 0 citations
How can a single monosaccharide control nearly every human cellular feature? This question has hounded the O-GlcNAc field since 1984. Despite identifying thousands of O-GlcNAc proteins, high-throughput datasets have only deepened the mystery. This Current Opinion highlights chemical biology tools (current as of 2023–20...
C. Fehl· Current Opinion in Chemical...· 0 citations
O-GlcNAcylation is an important post-translational modification that regulates numerous cellular processes, yet tools enabling selective removal of O-GlcNAc from individual proteins via endogenous O-GlcNAcase (OGA) in living cells remain limited. Here, we report De-O-GlcNAcylation-targeting chimeras (DOGTACs), a chemic...
O-GlcNAcylation is a ubiquitous post-translational modification across the mammalian proteome, yet determining how individual O-GlcNAcylation events control specific protein functions remains a central challenge. The O-GlcNAc cycle is governed by two enzymes: O-GlcNAc transferase (OGT), which installs O-GlcNAc, and O...
Bo-Wen Ma, Tong-Yang Xu, Zhi-Hao Guo et al.· Accounts of Chemical Researc...· 0 citations
An O-GlcNAcylation-targeting Chimera (OGTAC) is developed that recruits O-GlcNAc transferase (OGT) to the oncogenic transcription factor c-Myc, enabling targeted O-GlcNAcylation in living cells without globally perturbing cellular O-GlcNAcylation.
Tong-Yang Xu, Zhi-Hao Guo, K. S. Khan et al.· Cell Chemical Biology· 2 citations
Chemistry, through the synthesis of a radioactive sugar-donor, played a critical role in the discovery of O-GlcNAc and has been contributing indispensable tools ever since. Here, we cover where chemical methods have contributed to both the discovery and characterization of O-GlcNAc modifications. We will first discuss...
Rianna L. Haynie-Cion, Michelle Marie B. Helmeke, Dong-Ning Liu et al.· Glycobiology· 0 citations
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