Inhibitors of Tick-Borne Flavivirus Reproduction from
Structure-Based Virtual Screening
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Abstract
Flaviviruses
form a large family of enveloped viruses affecting
millions of people over the world. To date, no specific therapy was
suggested for the infected people, making the treatment exclusively
symptomatic. Several attempts were performed earlier for the design
of fusion inhibitors for mosquito-borne flaviviruses, whereas for
the tick-borne flaviviruses such design had not been performed. We
have constructed homology models of envelope glycoproteins of tick-transmitted
flaviviruses with the detergent binding pocket in the open state.
Molecular docking of substituted 1,4-dihydropyridines and pyrido[2,1-<i>b</i>][1,3,5]thiadiazines was made against these models, and
89 hits were selected for the in vitro experimental evaluation. Seventeen
compounds showed significant inhibition against tick-borne encephalitis
virus, Powassan virus, or Omsk hemorrhagic fever virus in the 50%
plaque reduction test in PEK cells. These compounds identified through
rational design are the first ones possessing reproduction inhibition
activity against tick-borne flaviviruses