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  3. Efficient inhibition of O-glycan biosynthesis using the hexosamine analog Ac5GalNTGc

Efficient inhibition of O-glycan biosynthesis using the hexosamine analog Ac5GalNTGc

  • Cell Chem Biol. 2021 May 20;28(5):699-710.e5. doi: 10.1016/j.chembiol.2021.01.017.
Shuen-Shiuan Wang 1,  Virginia Del Solar 1,  Xinheng Yu 1,  Aristotelis Antonopoulos 2,  Alan E Friedman 3,  Kavita Agarwal 4,  Monika Garg 4,  Syed Meheboob Ahmed 4,  Ahana Addhya 4,  Mehrab Nasirikenari 5,  Joseph T Lau 5,  Anne Dell 2,  Stuart M Haslam 2,  Srinivasa-Gopalan Sampathkumar 6,  Sriram Neelamegham 7
Affiliations

Affiliations

  • 1 Department of Chemical and Biological Engineering, State University of New York, 906 Furnas Hall, Buffalo, NY, USA.
  • 2 Department of Life Sciences, Imperial College London, London, UK.
  • 3 Department of Chemistry, State University of New York, Buffalo, NY, USA.
  • 4 Laboratory of Chemical Glycobiology, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.
  • 5 Department of Cellular and Molecular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
  • 6 Laboratory of Chemical Glycobiology, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India. Electronic address: gopalan@nii.ac.in.
  • 7 Department of Chemical and Biological Engineering, State University of New York, 906 Furnas Hall, Buffalo, NY, USA; Department of Medicine, State University of New York, Buffalo, NY, USA. Electronic address: neel@buffalo.edu.
PMID: 33609441 DOI: 10.1016/j.chembiol.2021.01.017
Abstract

There is a critical need to develop small-molecule inhibitors of mucin-type O-linked glycosylation. The best-known reagent currently is benzyl-GalNAc, but it is effective only at millimolar concentrations. This article demonstrates that Ac5GalNTGc, a peracetylated C-2 sulfhydryl-substituted GalNAc, fulfills this unmet need. When added to cultured leukocytes, breast cells, and prostate cells, Ac5GalNTGc increased cell-surface VVA binding by ∼10-fold, indicating truncation of O-glycan biosynthesis. Cytometry, mass spectrometry, and western blot analysis of HL-60 promyelocytes demonstrated that 50-80 μM Ac5GalNTGc prevented elaboration of 30%-60% of the O-glycans beyond the Tn-antigen (GalNAcα1-Ser/Thr) stage. The effect of the compound on N-glycans and glycosphingolipids was small. Glycan inhibition induced by Ac5GalNTGc resulted in 50%-80% reduction in leukocyte sialyl-Lewis X expression and L-/P-selectin-mediated rolling under flow conditions. Ac5GalNTGc was pharmacologically active in mouse. It reduced neutrophil infiltration to sites of inflammation by ∼60%. Overall, Ac5GalNTGc may find diverse applications as a potent inhibitor of O-glycosylation.

Keywords

O-glycan; cell adhesion; glycosylation; inflammation; inhibitor; mucin; neutrophil; selectin; sialyl-Lewis X; small molecule.

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