A Derivate of the Antibiotic Doxorubicin Is a Selective Inhibitor of Dengue and Yellow Fever Virus Replication In Vitro

Medientyp: E-Artikel
Titel: A Derivate of the Antibiotic Doxorubicin Is a Selective Inhibitor of Dengue and Yellow Fever Virus Replication In Vitro
Beteiligte: Kaptein, Suzanne J. F.; De Burghgraeve, Tine; Froeyen, Mathy; Pastorino, Boris; Alen, Marijke M. F.; Mondotte, Juan A.; Herdewijn, Piet; Jacobs, Michael; de Lamballerie, Xavier; Schols, Dominique; Gamarnik, Andrea V.; Sztaricskai, Ferenc; Neyts, Johan
Erschienen: American Society for Microbiology, 2010
Erschienen in: Antimicrobial Agents and Chemotherapy
Sprache: Englisch
DOI: 10.1128/aac.00686-10
ISSN: 0066-4804; 1098-6596
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Beschreibung: <jats:title>ABSTRACT</jats:title> <jats:p> A doxorubicin derivate, SA-17, that carries a squaric acid amide ester moiety at the carbohydrate (α- <jats:sc>l</jats:sc> -daunosaminyl) group was identified as a selective inhibitor of <jats:italic>in vitro</jats:italic> dengue virus (DENV) serotype 2 replication (50% effective concentration [EC <jats:sub>50</jats:sub> ] = 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 <jats:sub>50</jats:sub> = 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 <jats:italic>in vitro</jats:italic> 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 <jats:italic>Renilla</jats:italic> 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. </jats:p>
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