Assembling glyco-functionalized surfaces and membranes based on precision glycomacromolecules to study viral adhesion and inhibition

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Recently, we have established the solid phase synthesis of monodisperse, sequence-defined glycopolymers or so-called precision glycomacromolecules. These precision glycomacromolecules are multivalent mimics of natural oligo- and polysaccharides exhibiting high avidity and selective binding to protein receptors. We were especially interested in gaining deeper insights into the structure-property correlation of such polymeric sugar mimetics. So far, commonly used polymeric scaffolds are not well defined with regard to multivalency and sugar presentations thus hampering direct correlations between ligand structures and binding partner. Through the stepwise assembly of our precision glycomacromolecules, we obtain perfect control over the chemical structure. By controlled variations of the different structural parameters and detailed analysis of the multivalent binding of the precision glycomacromolecules to sugar-recognizing protein receptors, we have learned about the different binding modes of glycomacromolecules and how to design efficient glycomacromolecule ligands e.g. for bacteria targeting. With this approach we are able to design suitable ligands from the ground up without tedious empirical optimization as is usually done. Here, we will apply our synthetic platform for a series of glycomacromolecules targeting different viruses. Together with the Peters lab, we will synthesize glycomacromolecules presenting different mono-, di- and trisaccharide fragments of histo-blood group antigen (HBGA) epitopes and will probe the multivalent binding site of murine noroviruses (Peters and Taube labs) and human noroviruses (Hansman lab). From the Blaum lab, we will obtain di- and tetrasaccharide fragments of heparan sulfate, which will be conjugated to the macromolecular scaffolds and evaluated for their binding to Merkel cell polyomavirus MCPyV (with the Blaum lab) and human papillomavirus 16 (HPV-16) (with the Schelhaas lab). For both viral targets, the synthesis of heteromultivalent glycomacromolecules will be addressed combining the sGAG fragments with sialic acid (Sia) (for MCPyV) or non-sulfated glycosaminoglycans (GAG) fragments (for HPV), respectively. It is an intrinsic advantage of the solid phase assembly to give access to heteromultivalent glycomacromolecules. Here the simultaneous presentation of the different glycans on one polymeric backbone will be used to probe the potential cooperative binding of the glycans for viral activation.