Emerging chemical strategies for modulating protein O-GlcNAcylation.

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.