Preventing Influenza A Virus Infection by Mixed Inhibition of Neuraminidase and Hemagglutinin by Divalent Inhibitors

Divalent inhibitors of the neuraminidase enzyme (NA) of theInfluenza A virus were synthesized with vastly different spacers. The spacersvaried from 14 to 56 atoms and were relatively rigid by way of the buildingblocks and their connection by CuAAC. As the ligand for these constructs, a Delta 4-beta-D-glucoronide was used, which can be prepared formN-acetylglucosamine. This ligand showed good NA inhibitory potency but withroom for improvement by multivalency enhancement. The synthesizedcompounds showed modest potency enhancement in NA activity assays but asizeable potency increaseina4-daycytopathiceffect assay. Thedemonstration that the compounds can also inhibit hemagglutinin inaddition to NA may be the cause of the enhancement.