Selective Inhibition of Heparan Sulphate and Not Chondroitin Sulphate Biosynthesis by a Small, Soluble Competitive Inhibitor

Division of Cell Matrix Biology & Regenerative Medicine, Faculty of Biology, Medicine and Health, Michael Smith Building, The University of Manchester, Oxford Road, Manchester M13 9PT, UK

Center for Biomedical Mass Spectrometry, Boston University School of Medicine, 670 Albany Street, Boston, MA 02118, USA

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School of Chemistry & Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, UK

Authors to whom correspondence should be addressed.

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Current address: Department of Nephrology, Radboudumc, Geert Grooteplein 10, 6525 GA Nijmegen, The Netherlands.

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Current address: Nottingham Biodiscovery Institute, School of Medicine, University of Nottingham, Nottingham NG7 2RD, UK.

Academic Editors: Chiara Schiraldi, Donatella Cimini and Annalisa La Gatta

Int. J. Mol. Sci. 2021, 22(13), 6988; https://doi.org/10.3390/ijms22136988

Received: 24 May 2021 / Revised: 16 June 2021 / Accepted: 19 June 2021 / Published: 29 June 2021

(This article belongs to the Special Issue Glycosaminoglycans)

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Abstract

The glycosaminoglycan, heparan sulphate (HS), orchestrates many developmental processes. Yet its biological role has not yet fully been elucidated. Small molecule chemical inhibitors can be used to perturb HS function and these compounds provide cheap alternatives to genetic manipulation methods. However, existing chemical inhibition methods for HS also interfere with chondroitin sulphate (CS), complicating data interpretation of HS function. Herein, a simple method for the selective inhibition of HS biosynthesis is described. Using endogenous metabolic sugar pathways, Ac₄GalNAz produces UDP-GlcNAz, which can target HS synthesis. Cell treatment with Ac₄GalNAz resulted in defective chain elongation of the polymer and decreased HS expression. Conversely, no adverse effect on CS production was observed. The inhibition was transient and dose-dependent, affording rescue of HS expression after removal of the unnatural azido sugar. The utility of inhibition is demonstrated in cell culture and in whole organisms, demonstrating that this small molecule can be used as a tool for HS inhibition in biological systems. View Full-Text

Keywords: heparan sulfate; azido sugar; glycosaminoglycan; carbohydrate biosynthesis; small molecule inhibitor; biorthogonal chemistry

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MDPI and ACS Style

Maciej-Hulme, M.L.; Dubaissi, E.; Shao, C.; Zaia, J.; Amaya, E.; Flitsch, S.L.; Merry, C.L.R. Selective Inhibition of Heparan Sulphate and Not Chondroitin Sulphate Biosynthesis by a Small, Soluble Competitive Inhibitor. Int. J. Mol. Sci. 2021, 22, 6988. https://doi.org/10.3390/ijms22136988

AMA Style

Maciej-Hulme ML, Dubaissi E, Shao C, Zaia J, Amaya E, Flitsch SL, Merry CLR. Selective Inhibition of Heparan Sulphate and Not Chondroitin Sulphate Biosynthesis by a Small, Soluble Competitive Inhibitor. International Journal of Molecular Sciences. 2021; 22(13):6988. https://doi.org/10.3390/ijms22136988

Chicago/Turabian Style

Maciej-Hulme, Marissa L., Eamon Dubaissi, Chun Shao, Joseph Zaia, Enrique Amaya, Sabine L. Flitsch, and Catherine L. R. Merry. 2021. "Selective Inhibition of Heparan Sulphate and Not Chondroitin Sulphate Biosynthesis by a Small, Soluble Competitive Inhibitor" International Journal of Molecular Sciences 22, no. 13: 6988. https://doi.org/10.3390/ijms22136988

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Selective Inhibition of Heparan Sulphate and Not Chondroitin Sulphate Biosynthesis by a Small, Soluble Competitive Inhibitor

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