title: 3',5'Di-O-trityluridine inhibits in vitro flavivirus replication.
abstract: 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.
authors.affiliation: Virology and Chemotherapy, Rega Institute for Medical Research, K.U. Leuven, Leuven, Belgium.
authors.forename: Tine
authors.initials: T
authors.lastname: De Burghgraeve
authors.forename: Barbara
authors.initials: B
authors.lastname: Selisko
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kaptein
authors.forename: Grégory
authors.initials: G
authors.lastname: Chatelain
authors.forename: Pieter
authors.initials: P
authors.lastname: Leyssen
authors.forename: Yannick
authors.initials: Y
authors.lastname: Debing
authors.forename: Michael
authors.initials: M
authors.lastname: Jacobs
authors.forename: Arthur
authors.initials: A
authors.lastname: Van Aerschot
authors.forename: Bruno
authors.initials: B
authors.lastname: Canard
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D003715:Dengue / Q000188:drug therapy / Q000821:virology*; D003716:Dengue Virus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006801:Humans; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014320:Triphenylmethyl Compounds / Q000494:pharmacology*; D014529:Uridine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*; D015004:Yellow Fever / Q000188:drug therapy / Q000821:virology*; D015005:Yellow fever virus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology
chemical_list: C584012:3',5'-di-O-trityluridine; D000998:Antiviral Agents; D014320:Triphenylmethyl Compounds; D014764:Viral Proteins; D012324:RNA-Dependent RNA Polymerase; D014529:Uridine