Targeted Protein O-GlcNAcylation Using Bifunctional Small Molecules

  • J Am Chem Soc. 2024 Apr 10;146(14):9779-9789. doi: 10.1021/jacs.3c14380.
Bowen Ma  1 ,  Khadija Shahed Khan  1  2 ,  Tongyang Xu  1 ,  Josefina Xeque Amada  1 ,  Zhihao Guo  1 ,  Yunpeng Huang  1 ,  Yu Yan  1 ,  Henry Lam  3 ,  Alfred Sze-Lok Cheng  2 ,  Billy Wai-Lung Ng  1  4
Affiliations
  • 1. School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong.
  • 2. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong.
  • 3. Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Sai Kung, Hong Kong.
  • 4. Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong.
PMID: 38561350 DOI: 10.1021/jacs.3c14380
Abstract

Protein O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) plays a crucial role in regulating essential cellular processes. The disruption of the homeostasis of O-GlcNAcylation 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 the O-GlcNAcylation challenging. To address this, we have developed heterobifunctional small molecules, named O-GlcNAcylation TArgeting Chimeras (OGTACs), which enable protein-specific O-GlcNAcylation in living cells. OGTACs promote O-GlcNAcylation of proteins such as BRD4, CK2α, and EZH2 in cellulo by recruiting FKBP12F36V-fused O-GlcNAc transferase (OGT), with temporal, magnitude, and reversible control. Overall, the 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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