Chemoenzymatic Synthesis of Heparan Sulfate Oligosaccharides having a Domain Structure**

Abstract

Heparan sulfate (HS) has a domain structure in which regions that are modified by epimerization and sulfonation (NS domains) are interspersed by unmodified fragments (NA domains). There is data to support that domain organization of HS can regulate binding of proteins, however, such model has been difficult to probe. Here, we report a chemoenzymatic methodology that can provide HS oligosaccharides composed of two or more NS domains separated by NA domains of different length. It is based on the chemical synthesis of a HS oligosaccharide that enzymatically was extended by various GlcA-GlcNAc units and terminated in GlcNAc having an azido moiety at C-6 position. HS oligosaccharides having an azide and alkyne moiety could be assembled by copper catalyzed alkyne-azide cycloaddition to give compounds having various NS domains separated by unsulfonated regions. Competition binding studies showed that the length of an NA domain modulates the binding of the chemokines CCL5 and CXCL8.

Modified Heparins for Bone Repair

“…263 Very recently, Sun, Chopra and Boons reported a chemoenzymatic synthesis of an HS-like polysaccharide assembled from highly sulfated and undersulfated components, achieving "domains" of different sulfation, like natural HS. 266 Six days later, Baryal et al reported the development of a library of 64 synthetically prepared tetrasaccharides, from which was identified a high FGF2-binding molecule with low platelet factor-4 binding. 267 Assuming this binding translates into potentiation of useful biological activity, this approach is promising for the elucidation and generation of BMP2 potentiating glycosaminoglycans.…”