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bioRxiv · 10.1101/2023.06.09.544275

Targeted Protein O-GlcNAcylation Using Bifunctional Small Molecules

Ma, B.·Khan, K. S.·Xu, T.·Amada, J. X.·Guo, Z.·Yan, Y.·Cheng, A.·Ng, W.-L.
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Abstract

Protein O-linked {beta}-N-acetylglucosamine modification (O-GlcNAcylation) plays a crucial role in regulating essential cellular processes. The disruption of O-GlcNAcylation homeostasis has been linked to various human diseases, including cancer, diabetes, and neurodegeneration. However, there are limited chemical tools for protein- and site-specific O-GlcNAc modification, rendering the precise study of O-GlcNAcylation challenging. To address this, we have developed first-in-class heterobifunctional small molecules, named O-GlcNAcylation targeting chimeras (OGTACs), which enable protein-specific O-GlcNAcylation in cells. OGTACs promote O-GlcNAcylation of proteins such as BRD4, CK2, and EZH2 in cellulo by recruiting O-GlcNAc transferase (OGT), with temporal and magnitude control. Mass spectrometry data revealed that OGTACs induced site-selective O-GlcNAcylation of BRD4. Overall, OGTACs represent a promising approach for inducing protein-specific O-GlcNAcylation, thus enabling functional dissection and offering new directions for O-GlcNAc-targeting therapeutic development.

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Ma, B., Khan, K. S., Xu, T., Amada, J. X., Guo, Z., Yan, Y., Cheng, A., Ng, W.-L.. 2023-06-11. Targeted Protein O-GlcNAcylation Using Bifunctional Small Molecules. https://doi.org/10.1101/2023.06.09.544275

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