Efficient inhibition of O-glycan biosynthesis using the hexosamine analog Ac 5 GalNTGc.

Autor: Wang SS; Department of Chemical and Biological Engineering, State University of New York, 906 Furnas Hall, Buffalo, NY, USA., Solar VD; Department of Chemical and Biological Engineering, State University of New York, 906 Furnas Hall, Buffalo, NY, USA., Yu X; Department of Chemical and Biological Engineering, State University of New York, 906 Furnas Hall, Buffalo, NY, USA., Antonopoulos A; Department of Life Sciences, Imperial College London, London, UK., Friedman AE; Department of Chemistry, State University of New York, Buffalo, NY, USA., Agarwal K; Laboratory of Chemical Glycobiology, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India., Garg M; Laboratory of Chemical Glycobiology, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India., Ahmed SM; Laboratory of Chemical Glycobiology, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India., Addhya A; Laboratory of Chemical Glycobiology, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India., Nasirikenari M; Department of Cellular and Molecular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA., Lau JT; Department of Cellular and Molecular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA., Dell A; Department of Life Sciences, Imperial College London, London, UK., Haslam SM; Department of Life Sciences, Imperial College London, London, UK., Sampathkumar SG; Laboratory of Chemical Glycobiology, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India. Electronic address: gopalan@nii.ac.in., Neelamegham S; 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.
Jazyk: angličtina
Zdroj: Cell chemical biology [Cell Chem Biol] 2021 May 20; Vol. 28 (5), pp. 699-710.e5. Date of Electronic Publication: 2021 Feb 19.
DOI: 10.1016/j.chembiol.2021.01.017
Abstrakt: 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 Ac 5 GalNTGc, a peracetylated C-2 sulfhydryl-substituted GalNAc, fulfills this unmet need. When added to cultured leukocytes, breast cells, and prostate cells, Ac 5 GalNTGc 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 Ac 5 GalNTGc 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 Ac 5 GalNTGc resulted in 50%-80% reduction in leukocyte sialyl-Lewis X expression and L-/P-selectin-mediated rolling under flow conditions. Ac 5 GalNTGc was pharmacologically active in mouse. It reduced neutrophil infiltration to sites of inflammation by ∼60%. Overall, Ac 5 GalNTGc may find diverse applications as a potent inhibitor of O-glycosylation.
Competing Interests: Declaration of interests We do not have competing financial or non-financial interests.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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