Non-Toxic Virucidal Macromolecules Show High Efficacy Against Influenza Virus Ex Vivo and In Vivo

Influenza is one of the most widespread viral infections worldwide and represents a major public health problem. The risk of new pandemics remains high and it is likely that the development of a vaccine against strongly virulent influenza strains would take too long, hence would not help the initial fight of the pandemic. Antiviral drugs are available but they are far from ideal. Arguably, the ideal antiviral should target conserved viral domains and be virucidal, i.e. irreversibly inhibit viral infectivity. Here, we describe a new class of anti-influenza macromolecules that meets these criteria and displays exceedingly low toxicity. These compounds are based on a cyclodextrin core modified on its primary face with long hydrophobic linkers terminated in 6 sialyl-N-acetyllactosamine (6 SLN) or 3 SLN. SLN enables nanomolar inhibition of the viruses while the hydrophobic linkers confer irreversibility to the inhibition. We show that these cyclodextrins are effective against several human or avian influenza strains in vitro, as well as against a 2009 pandemic influenza strain ex vivo and in vivo. Importantly, replacing the hydrophobic linkers with hydrophilic ones results in molecules that are totally ineffective ex vivo, confirming the importance of the virucidal mechanism in the quest of a truly effective antiviral drug.