Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 4, Issue 9, Pages 869-874Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ml400226s
Keywords
Antiviral compounds; flavivirus; 1,4-dihydropyridines; pyrido[2,1-b][1,3,5]thiadiazines
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Funding
- Government of Russian Federation
- RFBR [11-03-01174a, 12-04-31317a]
- Program of Development of Lomonosov Moscow State University
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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-b][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.
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