title: A derivate of the antibiotic doxorubicin is a selective inhibitor of dengue and yellow fever virus replication in vitro.
abstract: A doxorubicin derivate, SA-17, that carries a squaric acid amide ester moiety at the carbohydrate (α-l-daunosaminyl) group was identified as a selective inhibitor of in vitro dengue virus (DENV) serotype 2 replication (50% effective concentration [EC(50)] = 0.34 ± 0.20 μg/ml [0.52 ± 0.31 μM]). SA-17 is markedly less cytostatic than the parent compound, resulting in a selectivity index value of ∼100. SA-17 also inhibits yellow fever virus 17D (YFV-17D) replication (EC(50) = 3.1 ± 1.0 μg/ml [4.8 ± 1.5 μM]), although less efficiently than DENV replication, but proved inactive against a variety of enveloped and nonenveloped viruses. SA-17 inhibits in vitro flavivirus replication in a dose-dependent manner, as was assessed by virus yield reduction assays and quantification of viral RNA by means of real-time quantitative reverse transcriptase PCR (RT-qPCR) (∼2 to 3 log reduction). The anti-DENV activity was confirmed using a Renilla luciferase-expressing dengue reporter virus. Time-of-drug-addition studies revealed that SA-17 acts at the very early stages of the viral replication cycle (i.e., virus attachment and/or virus entry). This observation was corroborated by the observation that SA-17, unlike the nucleoside analogue ribavirin, does not inhibit the replication of DENV subgenomic replicons. Preincubation of high-titer stocks of DENV or YFV-17D with ≥5 μg/ml SA-17 resulted in 100% inhibition of viral infectivity (≥3 log reduction). SA-17, however, did not prove virucidal.
authors.affiliation: Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors.forename: Suzanne J F
authors.initials: SJ
authors.lastname: Kaptein
authors.forename: Tine
authors.initials: T
authors.lastname: De Burghgraeve
authors.forename: Mathy
authors.initials: M
authors.lastname: Froeyen
authors.forename: Boris
authors.initials: B
authors.lastname: Pastorino
authors.forename: Marijke M F
authors.initials: MM
authors.lastname: Alen
authors.forename: Juan A
authors.initials: JA
authors.lastname: Mondotte
authors.forename: Piet
authors.initials: P
authors.lastname: Herdewijn
authors.forename: Michael
authors.initials: M
authors.lastname: Jacobs
authors.forename: Xavier
authors.initials: X
authors.lastname: de Lamballerie
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
authors.forename: Andrea V
authors.initials: AV
authors.lastname: Gamarnik
authors.forename: Ferenc
authors.initials: F
authors.lastname: Sztaricskai
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D003716:Dengue Virus / Q000187:drug effects*; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000494:pharmacology*; D012367:RNA, Viral / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014779:Virus Replication / Q000187:drug effects*; D015005:Yellow fever virus / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D012367:RNA, Viral; D004317:Doxorubicin