Chemoenzymatic synthesis and application of glycopolymers containing multivalent sialyloligosaccharides with a poly(L-glutamic acid) backbone for inhibition of infection by influenza viruses

Abstract

Highly water-soluble glycopolymers with poly(α-L-glutamic acid) (PGA) backbones carrying multivalent sialyl oligosaccharides units were chemoenzymatically synthesized as polymeric inhibitors of infection by human influenza viruses. p-Aminophenyl disaccharide glycosides were coupled with γ-carboxyl groups of PGA side chains and enzymatically converted to Neu5Acα2-3Galβ1-4GlcNAcβ-, Neu5Acα2-6Galβ1-4GlcNAcβ-, Neu5Acα2-3Galβ1-3GalNAcα-, and Neu5Acα2-3Galβ1-3GalNAcβ- units, respectively, by α2,3- or α2,6-sialytransferases. The glycopolymers synthesized were used for neutralization of human influenza A and B virus infection as assessed by measurement of the degree of cytopathic inhibitory effect in virus-infected MDCK cells. Among the glycopolymers tested, α2,6-sialo-PGA with a high molecular weight (260 kDa) most significantly inhibited infection by an influenza A virus, strain A/Memphis/1/71 (H3N2), which predominantly binds to α2-6 Neu5Ac residue. The α2,6-sialo-PGA also inhibited infection by an influenza B virus, B/Lee/40. The binding preference of viruses to terminal sialic acids was affected by core determinants of the sugar chain, Galβ1-4GlcNAcβ- or Galβ1-3GalNAcα/β- units. Inhibition of infection by viruses was remarkably enhanced by increasing the molecular weight and sialic acid content of glycopolymers.