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Selective Inhibition of Heparan Sulphate and Not Chondroitin Sulphate Biosynthesis by a Small, Soluble Competitive InhibitorMaciej-Hulme, Marissa L.; orcid: 0000-0001-5615-4197; email: firstname.lastname@example.org; Dubaissi, Eamon; email: email@example.com; Shao, Chun; email: Chun.Shao@bms.com; Zaia, Joseph; orcid: 0000-0001-9497-8701; email: firstname.lastname@example.org; Amaya, Enrique; orcid: 0000-0002-1805-8548; email: email@example.com; Flitsch, Sabine L.; email: Sabine.Flitsch@manchester.ac.uk; Merry, Catherine L. R.; orcid: 0000-0002-3490-2809; email: firstname.lastname@example.org (MDPI, 2021-06-29)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.