Chemoenzymatic Synthesis of Glycan-arranged Polymeric Inhibitors against Influenza Virus Infection

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  • Ogata Makoto
    Department of Applied Biological Chemistry, Faculty of Agriculture, Shizuoka University
  • Murata Takeomi
    Department of Applied Biological Chemistry, Faculty of Agriculture, Shizuoka University
  • Park Enoch Y.
    Department of Bioscience, Graduate School of Science and Technology, Shizuoka University
  • Usui Taichi
    Department of Applied Biological Chemistry, Faculty of Agriculture, Shizuoka University Department of Bioscience, Graduate School of Science and Technology, Shizuoka University

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  • 糖鎖を活用したインフルエンザウイルス感染阻止剤の酵素化学合成

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Highly water-soluble, artificial glycopolypeptides with a γ-polyglutamic acid (γ-PGA) backbone derived from Bacillus subtilis and multivalent sialyloligosaccharide units have been chemoenzymatically synthesized as potential polymeric inhibitors of infection by influenza virus. 5-Trifluoroacetamidopentyl β-N-acetyllactosaminide (1) was enzymatically synthesized from N-acetyllactosamine (LacNAc: Galβ1-4GlcNAc) by cellulase-mediated condensation with 5-trifluoroacetamido-1-pentanol. Next, enzymatic sugar elongation of the LacNAc unit to 1 was carried out by consecutive use of β1,3-N-acetylglucosaminyltransferase II (β3GnTII) and β1,4-galactosyltransferase I (β4GalTI) to produce tetra- and hexasaccharide glycosides (2 and 3) with tandem and triplet LacNAc repeats. After deacetylation, the resulting 5-aminopentyl di-, tetra- and hexasaccharide glycosides (4-6) were coupled to the α-carboxy groups of the γ-PGA side chains. Next, in order to synthesize an artificial sialoglycopolypeptide, we developed a large-scale production of rat α2,6-sialyltransferases (α2,6-SiaT). The α2,6-SiaT was expressed in fifth instar silkworm larval hemolymph using recombinant both cysteine protease- and chitinase-deficient Bombyx mori nucleopolyhedrovirus (BmNPV-CP--Chi-) bacmid. The expressed α2,6-SiaT and commercially available α2,3-SiaT were used for sialylation of asialoglycopolypeptides (7-9). The structure-activity relationship of the resulting α2,3/6-sialoglycopolypeptides (10-15) with different glycans in the array has been investigated by focus-forming and solid-phase binding assays. The avian viruses specifically bound to glycopolypeptides carrying a short sialo-glycan with higher affinity than to a long glycan. In contrast, human viruses preferentially bound to long α2,3/6 sialylated glycan with LacNAc repeats in the receptors. Our strategy provides a facile way to design strong polymeric inhibitors of infection by avian and human influenza viruses.

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