Abstract In recent decades, epidemics and pandemics have multiplied throughout the world, with viruses generally being the primary agents responsible. Among these, influenza viruses play a key role, as they cause severe respiratory distress, representing a major threat to public health. To enhance the response to viral disease outbreaks, there is a need for ready-to-use broad-spectrum antivirals. We have engineered macromolecules (named CD-SA) consisting of a β-cyclodextrin (CD) scaffold modified with hydrophobic linkers in the primary face, onto which unitary sialic acid (SA) epitopes are covalently grafted, this to mimic influenza virus host receptors. In this study, we demonstrated that CD-SA, with a unitary SA, without extensive polysaccharides or specific connectivity, acts as a potent virucidal antiviral against several variants of human influenza type A and type B viruses. We also assessed the genetic barrier to resistance of CD-SA in vitro and successfully delayed emergence of resistance by combining CD-SA with interferon-λ1 (IFN λ1). Finally, we completed the characterization of the antiviral activity by conducting both ex vivo and in vivo studies, demonstrating a potent antiviral effect in human airway epithelia and in a mouse model of infection, higher than that of Oseltamivir, a currently approved anti-influenza antiviral.

Development of Broad-spectrum β-cyclodextrins-Based Nanomaterials Against Influenza Viruses