4.7 Article

Antiviral Mechanism of Virucidal Sialic Acid Modified Cyclodextrin

Journal

PHARMACEUTICS
Volume 15, Issue 2, Pages -

Publisher

MDPI
DOI: 10.3390/pharmaceutics15020582

Keywords

influenza; hemagglutinin; 6' SLN; hydrophobic linker; antiviral mechanism; virucidal; membrane interaction

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We have reported that CD-6'SLN irreversibly deactivates virions and improves mice survival in H1N1 infection model. CD-6'SLN interacts with the viral envelope protein HA, but not with NA, inhibiting influenza virus through an extracellular mechanism. Our findings suggest that combining viral protein-specific epitopes with hydrophobic linkers provides a strategy for developing antiviral drugs.
We have reported that CD-6'SLN [6-sialyllactosamine (6'SLN)-modified beta-cyclodextrin (CD)] can be a potential anti-influenza drug because it irreversibly deactivates virions. Indeed, in vivo, CD-6'SLN improved mice survival in an H1N1 infection model even when administered 24 h post-infection. Although CD-6'SLN was designed to target the viral envelope protein hemagglutinin (HA), a natural receptor of 6'SLN, it remains unclear whether other targets exist. In this study, we confirm that CD-6'SLN inhibits the influenza virus through an extracellular mechanism by interacting with HA, but not with neuraminidase (NA), despite the latter also having a binding pocket for the sialyl group. We find that CD-6'SLN interacts with the viral envelope as it elicits the release of a fluorophore embedded in the membrane. Two similar compounds were designed to test separately the effect of 6'SLN and of the undecyl moiety that links the CD to 6'SLN. Neither showed any interaction with the membrane nor the irreversible viral inhibition (virucidal), confirming that both components are essential to membrane interaction and virucidal action. Unlike similar antiviral cyclodextrins developed against other viruses, CD-6'SLN was not able to decapsulate viral RNA. Our findings support that combining viral protein-specific epitopes with hydrophobic linkers provides a strategy for developing antiviral drugs with a virucidal mechanism.

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