Inhibitors of tick-borne flavivirus reproduction from structure-based virtual screening.

Supporting InformationABSTRACT: Flaviviruses form a large family of enveloped viruses affecting millions of peopleover the world. To date, no specific therapy was suggested for the infected people, making thetreatment exclusively symptomatic. Several attempts were performed earlier for the design offusion inhibitors for mosquito-borne flaviviruses, whereas for the tick-borne flaviviruses suchdesign had not been performed. We have constructed homology models of envelopeglycoproteins of tick-transmitted flaviviruses with the detergent binding pocket in the openstate. Molecular docking of substituted 1,4-dihydropyridines and pyrido[2,1-b][1,3,5]-thiadiazines was made against these models, and 89 hits were selected for the in vitroexperimental evaluation. Seventeen compounds showed significant inhibition against tick-borneencephalitis virus, Powassan virus, or Omsk hemorrhagic fever virus in the 50% plaquereduction test in PEK cells. These compounds identified through rational design are the first ones possessing reproductioninhibition activity against tick-borne flaviviruses.KEYWORDS: Antiviral compounds, flavivirus, 1,4-dihydropyridines, pyrido[2,1-b][1,3,5]thiadiazines