Thioglycosides Are efficient metabolic decoys of glycosylation that reduce selectin dependent leukocyte adhesion
File(s)CELL-CHEMICAL-BIOLOGY-D-18-00127_R1.pdf (2.85 MB)
Accepted version
Author(s)
Type
Journal Article
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.
Date Issued
2018-12-20
Date Acceptance
2018-09-25
Citation
Cell Chemical Biology, 2018, 25, pp.1-14
ISSN
2451-9448
Publisher
Elsevier Inc.
Start Page
1
End Page
14
Journal / Book Title
Cell Chemical Biology
Volume
25
Copyright Statement
© 2018 Elsevier Ltd. All rights reserved. This manuscript is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
Sponsor
Biotechnology and Biological Sciences Research Council (BBSRC)
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/30344053
PII: S2451-9456(18)30332-5
Grant Number
BB/K016164/1
Subjects
N-glycan
decoy
fluid shear
glycosides
glycosylation
inflammation
leukocyte-endothelial adhesion
selectins
small-molecule inhibitors
thioglycoside
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2018-10-18