3′,5′Di-O-trityluridine inhibits in vitro flavivirus replication

The dengue fever virus (DENV) and the yellow fever virus (YFV) are members of the genus flavivirus in the family Flaviviridae. An estimated 50–100 million cases of DENV infections occur each year and approximately half a million patients require hospitalization. There is no vaccine or effective antiviral treatment available. There is an urgent need for potent and safe inhibitors of DENV replication; ideally such compounds should have broad-spectrum activity against flaviviruses. We here report on the in vitro activity of 3′,5′di-O-trityluridine on flavivirus replication. The compound results in a dose-dependent inhibition of (i) DENV- and YFV-induced cytopathic effect (CPE) (EC50 values in the low micromolar range for the 4 DENV serotypes), (ii) RNA replication (DENV-2 EC50 = 1.5 μM; YFV-17D EC50 = 0.83 μM) and (iii) viral antigen production. Antiviral activity was also demonstrated in DENV subgenomic replicons (which do not encode the structural viral proteins) (EC50 = 2.3 μM), indicating that the compound inhibits intracellular events of the viral replication cycle. Preliminary data indicate that the molecule may inhibit the viral RNA-dependent RNA polymerase.

► In vitro activity of 3′,5′di-O-trityluridine on flavivirus replication.
► Inhibition of DENV-induced CPE (EC50: low micromolar range).
► Inhibition of the RNA-dependent RNA polymerase activity of protein NS5.
► Kinetic analysis of inhibition of the RdRp indicates inhibition of RNA elongation.
► It does not compete with UTP during RNA elongation on DENV-specific templates.