Chemoenzymatic Synthesis of Sialoglycopolypeptides As Glycomimetics to Block Infection by Avian and Human Influenza Viruses

Abstract

We designed a series of gamma-polyglutamic acid (gamma-PGA)-based glycopolypeptides carrying long/short alpha2,3/6 sialylated glycans to act inhibitors of the influenza virus. As an alternative design, sialoglycopolypeptides carrying long-spacer linked glycans were engineered by replacement of the N-acetyllactosamine (LN) unit by an alkyl chain. The structure-activity relationship of the resulting sialoglycopolypeptides with different glycans in the array has been investigated by in vitro and in vivo infection experiments. The avian viruses specifically bound to glycopolypeptides carrying a short sialoglycan with higher affinity than to a long glycan. In contrast, human viruses, preferentially bound not only to long alpha2,3/6 sialylated glycan with LN repeats in the receptors, but also to more spacer-linked glycan in which the inner sugar has been replaced by a nonsugar structural unit such as a pentylamido group. Taken together, our results indicate that a spaced tandem/triplet pentylamido repeat is a good mimetic of a tandem/triplet LN repeat. Our strategy provides a facile way to design strong polymeric inhibitors of infection by avian and human influenza viruses.

Expression and purification of bioactive hemagglutinin protein of highly pathogenic avian influenza A (H5N1) in silkworm larvae

“…Assay for direct binding of rHA to its receptor ␥-Polyglutamic acid (␥-PGA; MW 990,000) from Bacillus subtilis was a kind gift from Meiji Food Materia Co. Ltd. (Tokyo, Japan). Poly{Neu5Ac␣2,3LacNAc␤-O[(CH 2 ) 5 NHCO] 2 (CH 2 ) 5 NH-/␥-PGA} and poly{Neu5Ac␣2,6LacNAc␤-O[(CH 2 ) 5 NHCO] 2 (CH 2 ) 5 NH-/␥-PGA} were synthesized as described previously described method (Ogata et al, 2009). The binding capacity of purified rHA for these poly-sugar chains was tested using a previously described direct binding assay (Ogata et al, 2009).…”

“…Poly{Neu5Ac␣2,3LacNAc␤-O[(CH 2 ) 5 NHCO] 2 (CH 2 ) 5 NH-/␥-PGA} and poly{Neu5Ac␣2,6LacNAc␤-O[(CH 2 ) 5 NHCO] 2 (CH 2 ) 5 NH-/␥-PGA} were synthesized as described previously described method (Ogata et al, 2009). The binding capacity of purified rHA for these poly-sugar chains was tested using a previously described direct binding assay (Ogata et al, 2009). ␥-PGA and glycopolymers (0.5 nM, 50 L/well) in 50 mM sodium acetate buffer (pH 4.0) were briefly immobilized on polystyrene Universal-Bind microplates (Corning Incorporated, New York, NY, USA) using an ultraviolet irradiation method.…”

Recent Developments in Neoglycopeptide Synthesis

“…Conversion of heterogeneous glycans to a single residue by enzymatic degradation and subsequent transglycosylation allows glycoprotein remodeling, although the transglycosylation step often suffers from low yield. Usui et al [137,138] designed artificial sialoglycopolypeptides as inhibitors of avian and human influenza virus infection. Their syntheses entailed consecutive enzymatic additions of GlcNAc and galactose residues with a differing number of sugar units built on an alkyl chain spacer linking them to a c-polyglutamic acid backbone.…”

Effects of Dietary Sialic Acid in n-3 Fatty Acid-Deficient Dams during Pregnancy and Lactation on the Learning Abilities of Their Pups after Weaning

“…It is thought that sialic acids play a central role in protection from infection by trapping bacteria from the environment because they are abundant in milk, especially colostrums (2-4). There are many reports of sialic acids and their functional aspects with respect to protection, such as against influenza viruses (5,6).…”