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

作者：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^*

来源：Antimicrobial Agents and Chemotherapy, 2010, 54(12): 5269-5280.

DOI：10.1128/AAC.00686-10

A doxorubicin derivate, SA-17, that carries a squaric acid amide ester moiety at the carbohydrate (alpha-L-daunosaminyl) group was identified as a selective inhibitor of in vitro dengue virus (DENV) serotype 2 replication (50% effective concentration [EC50] = 0.34 +/- 0.20 mu g/ml [0.52 +/- 0.31 mu M]). SA-17 is markedly less cytostatic than the parent compound, resulting in a selectivity index value of similar to 100. SA-17 also inhibits yellow fever virus 17D (YFV-17D) replication (EC50 = 3.1 +/- 1.0 mu g/ml [4.8 +/- 1.5 mu M]), 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) (similar to 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 mu g/ml SA-17 resulted in 100% inhibition of viral infectivity (>= 3 log reduction). SA-17, however, did not prove virucidal.

• 出版日期2010-12
• 单位河北医科大学