A derivate of the antibiotic doxorubicin is a selective inhibitor of dengue and yellow fever virus replication in vitro

3. KAPTEIN SJ, DE BURGHGRAEVE, FROEYEN, PASTORINO , ALEN, MONDOTTE JA, HERDEWIJN, JACOBS M, DE LAMBALLERIE, SCHOLS, GAMARNIK AV, SZTARICSKAI, NEYTS.

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY

AMER SOC MICROBIOLOGY

Lugar: WASHINGTON DC; Año: 2010 p. 5269 - 5280

0066-4804

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 (EC50 = 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 YFV-17D replication (EC50 = 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 non-enveloped 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 RT-qPCR (~2-3 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. Pre-incubation 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.