A new class of anti-influenza macromolecules were synthesized based on a cyclodextrin to target conserved viral domains irreversibly.
6’ sialyl-N-acetyllactosamine (6’SLN) and 3’ sialyl-N-acetyllactosamine (3’SLN), that bind
to hemagglutinin (HA) trimers of influenza strains with high affinity, were grafted onto the primary face of β-cyclodextrins through a series of different linkers. Since each HA trimer has three sialic acid binding pockets, β-CD was modified with three trisachharides.
β-CDs bearing a sufficiently long, hydrophobic linker and 6’SLN end-group showed strong inhibitory activity in vitro against infection with influenza A/NL/09, having EC50 values in the nanomolar range. On the other hand, the β-CD with a shorter linker, poorly protected from the infection.
In vivo experiments were conducted with BALB/c mice administered first with the compound effective in vitro (25 μg/mouse) and immediately after with A/NL/09 (100 infectious particles/mouse) via the intranasal route. At 2 dpi, half of the mice were randomly euthanized and the rest of the mice retreated with the compound. The second group of mice was euthanized at 4 dpi. Viral titers were quantified from broncho-alveolar lavages (BAL). Significant decrease of viral titers was observed at day 2 and 4 post-infection in treated mice. The antiviral activity of the compound also significantly diminished mice morbidity with a significant preservation of both body weight and body temperature compared to untreated mice. Collectively, these results suggest a potent capacity of the CD-based compound to prevent in vivo infection.
Supramolecular Carbohydrate Chemistry, just accepted paper https://doi.org/10.1101/2020.03.18.996678.