Ligand-Directed Self-Assembling Chimeras for Targeted Protein O-GlcNAcylation
Precise control of protein-specific O-GlcNAcylation in cells remains a major challenge. Chemically induced proximity (CIP) offers a promising path forward, but its application to targeted protein O-GlcNAcylation has been limited by the lack of ligands that can bind the O-GlcNAc transferase (OGT) without inhibiting its catalytic function. Here, we repurpose a potent OGT inhibitor into a noninhibitory covalent probe using ligand-directed release chemistry (LDR). The resulting ligands covalently label OGT while preserving its enzymatic activity. Building on this scaffold, we developed a self-assembling O-GlcNAcylation Targeting Chimera (OGTAC) that recruits OGT to its native substrate casein kinase IIα (CK2α) in living cells, selectively elevating CK2α O-GlcNAcylation without affecting global modification levels. This new class of self-assembling chimeras covalently engages OGT to induce protein-specific O-GlcNAcylation, offering a versatile platform for dissecting and controlling this essential modification in living cells. Our findings open the door to next-generation OGTACs and related therapeutic strategies for the targeted modulation of the O-GlcNAc signaling.
Authors
- Wai‐Lung Ng (ORCID: https://orcid.org/0000-0003-2892-6318)
- Stephan Scheeff (ORCID: https://orcid.org/0000-0001-7791-9670)
- Clive Yik‐Sham Chung (ORCID: https://orcid.org/0000-0003-1382-719X)
- Yuanpei Li (ORCID: https://orcid.org/0000-0002-4015-646X)
- Itaru Hamachi (ORCID: https://orcid.org/0000-0002-3327-3916)
- Tomonori Tamura (ORCID: https://orcid.org/0000-0003-1648-9296)
- Yalun Xie (ORCID: https://orcid.org/0000-0002-9439-7111)
- Tongyang Xu (ORCID: https://orcid.org/0000-0002-4934-8548)
- Bowen Ma (ORCID: https://orcid.org/0009-0004-3177-9966)
- Richard K. Lo
- Yunpeng Huang (ORCID: https://orcid.org/0000-0002-8710-9062)
- Yao Qin
- Khadija Shahed Khan (ORCID: https://orcid.org/0000-0001-7591-6601)
- Zhihao Guo (ORCID: https://orcid.org/0009-0003-5146-2424)
- S. Yu (ORCID: https://orcid.org/0000-0002-0851-7392)
- Hillary Yui-Yan Yip
Institutions
- Chinese University of Hong Kong (HK)
- Kyoto University (JP)
- Guangdong-Hongkong-Macau Joint Laboratory of Collaborative Innovation for Environmental Quality (CN)
- Neuroscience Institute (IT)
- State Key Laboratory of Synthetic Chemistry (CN)
- University of Hong Kong (HK)
Publication Details
- Journal
- ACS Chemical Biology
- Published
- 2025-12-05
- DOI
- https://doi.org/10.1021/acschembio.5c00684
- Citations
- 1
- Primary Topic
- Glycosylation and Glycoproteins Research
- Type
- article
- Field-Weighted Citation Impact
- 0.81