Chemoenzymatic Synthesis of Heparan Sulfate Oligosaccharides having a Domain Structure

Abstract

AbstractHeparan sulfate (HS) have domain structures in which regions that are substantially modified by epimerization and sulfation (NS domains) are interspersed by unmodified fragments (NA domains). There is data to support that the domain structure of HS can regulate protein binding, however, such a binding mode 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 sulfated HS oligosaccharide that enzymatically could be extended by various GlcA-GlcNAc units and terminated in a GlcNAc-6N3 moiety. HS oligosaccharides having an azide and alkyne moiety could assembled by copper catalyzed alkyne-azide cycloaddition (CuAAC) to give compounds having various NS domains separated by unsulfated regions. Competition binding studies showed that the length of an NA domain modulates the binding of the chemokines CCL5 and CXCL8.