PhD defence: Chemoenzymatic Synthesis of Heparan Sulfate Oligosaccharides having domain structures

PhD defence of L. Sun

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Heparan sulfate (HS) has a domain structure in which sulfated domains (NS) are interspersed by unmodified fragments (NA domains). There is data to support that domain organization of HS can regulate binding of proteins, however, such a model has been difficult to probe.

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. 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. This methodology was applied to prepare well-defined multimeric heparin mimetics composed of as many as 27 monosaccharides.

Heparin mimetics were examined for their ability to inhibit the binding of the spike of SARS-CoV-2 to immobilized heparin or Vero E6 cells. It was found that increasing the number of repeating units resulted in large increases in inhibitory potential and a tetravalent compound had similar potency compared to heparin.

The data support that well-defined heparin mimetics can be developed to inhibit the attachment of SARS-CoV-2 to the target cell. We describe a modular synthetic methodology that can provide HS oligosaccharide having N-acetyl and N-sulfate moieties.

Start date and time
End date and time
Location
Academiegebouw, Domplein 29
PhD candidate
L. Sun
Dissertation
Chemoenzymatic Synthesis of Heparan Sulfate Oligosaccharides having domain structures
PhD supervisor(s)
prof. dr. G.J.P.H. Boons