Pan Respiratory Antiviral Macromolecule from Sialylglycopeptide

N-Glycans on cell surfaces are recognized by respiratory viruses to induce infection. Development of viral inhibitors that mimic viral natural receptors is a known and attractive strategy that tends to exhibit low toxicity. We have shown strategies to render this strategy more potent by conferring to the molecules a virucidal mechanism via a long and flexible hydrophobic linker. So far, the most successful approach has been a molecule based on cyclodextrin functionalized with Neu5Acα2-6Galβ1-4GlcNAc (6′SLN). Unfortunately, this glycan requires complex synthesis and, therefore, is expensive. Here, we designed an inexpensive multivalent entry inhibitor by modifying the primary alcohol of β-cyclodextrin (CD) with egg-derived sialylglycopeptide (SGP). The resulting macromolecule demonstrates nanomolar inhibition against sialic acid-dependent human influenza viruses and submicromolar inhibition against heparan sulfate-dependent viruses (RSV and SARS-CoV-2), overall outperforming the 6′SLN-functionalized antiviral. We also showed that the potency of the antiviral can be substantially increased by using sulfated versions of the SGP. The compound also shows significant anti-inflammatory properties based on its ability to inhibit the production of nitric oxide (NO) in lipopolysaccharide-induced RAW264.7 macrophages. Overall, this macromolecule could serve as a potential agent for the development of pan respiratory antivirals, and this strategy may contribute to the design of inhibitors incorporating more complex sugars.