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Cell Chem Biol. 2018 Dec 20;25(12):1519-1532.e5. doi: 10.1016/j.chembiol.2018.09.012. Epub 2018 Oct 18.

Thioglycosides Are Efficient Metabolic Decoys of Glycosylation that Reduce Selectin Dependent Leukocyte Adhesion.

Author information

1
Department of Chemical and Biological Engineering, State University of New York, 906 Furnas Hall, Buffalo, NY 14260, USA.
2
TumorEnd LLC, Louisiana Emerging Technology Center, 340 East Parker Drive, Suite 246, Baton Rouge, LA 70803, USA.
3
Department of Chemical and Biological Engineering, State University of New York, 906 Furnas Hall, Buffalo, NY 14260, USA; Clinical & Translational Research Center and State University of New York, Buffalo, NY 14260, USA.
4
Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
5
Department of Chemistry, State University of New York, Buffalo, NY 14260, USA.
6
Department of Cellular and Molecular Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
7
Department of Chemical and Biological Engineering, State University of New York, 906 Furnas Hall, Buffalo, NY 14260, USA; TumorEnd LLC, Louisiana Emerging Technology Center, 340 East Parker Drive, Suite 246, Baton Rouge, LA 70803, USA. Electronic address: klmatta40@gmail.com.
8
Department of Chemical and Biological Engineering, State University of New York, 906 Furnas Hall, Buffalo, NY 14260, USA; Clinical & Translational Research Center and State University of New York, Buffalo, NY 14260, USA. Electronic address: neel@buffalo.edu.

Abstract

Metabolic decoys are synthetic analogs of naturally occurring biosynthetic acceptors. These compounds divert cellular biosynthetic pathways by acting as artificial substrates that usurp the activity of natural enzymes. While O-linked glycosides are common, they are only partially effective even at millimolar concentrations. In contrast, we report that N-acetylglucosamine (GlcNAc) incorporated into various thioglycosides robustly truncate cell surface N- and O-linked glycan biosynthesis at 10-100 μM concentrations. The >10-fold greater inhibition is in part due to the resistance of thioglycosides to hydrolysis by intracellular hexosaminidases. The thioglycosides reduce β-galactose incorporation into lactosamine chains, cell surface sialyl Lewis-X expression, and leukocyte rolling on selectin substrates including inflamed endothelial cells under fluid shear. Treatment of granulocytes with thioglycosides prior to infusion into mouse inhibited neutrophil homing to sites of acute inflammation and bone marrow by ∼80%-90%. Overall, thioglycosides represent an easy to synthesize class of efficient metabolic inhibitors or decoys. They reduce N-/O-linked glycan biosynthesis and inflammatory leukocyte accumulation.

KEYWORDS:

N-glycan; decoy; fluid shear; glycosides; glycosylation; inflammation; leukocyte-endothelial adhesion; selectins; small-molecule inhibitors; thioglycoside

PMID:
30344053
PMCID:
PMC6474417
[Available on 2019-12-20]
DOI:
10.1016/j.chembiol.2018.09.012
[Indexed for MEDLINE]

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