The virus surface is anchored with different glycoproteins to accomplish the infection cycle. Glycobiomaterials designed to synergistically inhibit two or more virus surface proteins could address the bottlenecks in targeting virus infections. This is exemplified by this current study where low molecular weight heteromultivalent glycopolymers are designed which show their promise for translational applications against influenza A virus (IAV) infections.

IAV infections have been devastating causing 3-5 million cases of several illnesses and around half a million deaths per year globally. Among the two surface-anchored glycoproteins of IAV, hemagglutinin (HA) is responsible for the virus adhesion on the cell surface by sialoglycan binding, while neuraminidase (NA) is a sialidase-cleaving enzyme for sialic acid, thereby enabling virus motility and the release of newly produced virions from the cell surface. Heteromultivalent glycopolymers are prepared by conjugating sialic acid (SA) and zanamivir (ZA) derivatives on the biocompatible polyglycerol (PG) backbone. Irrespective of the IAV subtypes, the virus binding inhibition data suggest better adsorption of heteromultivalent polymer than homomultivalent analogs onto the virus surface. We demonstrate that the optimal presentation of ZA and SA on PG polymer can efficiently inhibit the propagation of different IAV strains at very low nanomolar concentrations in vitro with > 99.9 % infection inhibition, which is 3-4 folds more effective than the commercial ZA drug. Also, in the human lung post-infection model, the heteromultifunctional glycopolymer remains more potent than the commercial ZA drug or homomultivalent analogs and their physical mixtures.