Dual-Action Heteromultivalent Glycopolymers Stringently Block and Arrest Influenza A Virus Infection In Vitro and Ex Vivo

Here, we demonstrate the concerted inhibition of differentinfluenzaA virus (IAV) strains using a low-molecular-weight dual-action linearpolymer. The 6 '-sialyllactose and zanamivir conjugates of linearpolyglycerol are optimized for simultaneous targeting of hemagglutininand neuraminidase on the IAV surface. Independent of IAV subtypes,hemagglutination inhibition data suggest better adsorption of theheteromultivalent polymer than homomultivalent analogs onto the virussurface. Cryo-TEM images imply heteromultivalent compound-mediatedvirus aggregation. The optimized polymeric nanomaterial inhibits >99.9%propagation of various IAV strains 24 h postinfection in vitro at low nM concentrations and is up to 10000x more effectivethan the commercial zanamivir drug. In a human lung ex vivo multicyclic infection setup, the heteromultivalent polymer outperformsthe commercial drug zanamivir and homomultivalent analogs or theirphysical mixtures. This study authenticates the translational potentialof the dual-action targeting approach using small polymers for broadand high antiviral efficacy.

Automated summary

In this study, a low-molecular-weight dual-action linear polymer is used to successfully inhibit different strains of influenza A virus. The optimized polymer targets both hemagglutinin and neuraminidase on the virus surface, leading to effective inhibition of virus propagation. The polymer is significantly more effective than the commercial drug zanamivir, demonstrating its translational potential for broad and high antiviral efficacy.