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

Suzanne J F Kaptein, Tine De Burghgraeve, Mathy Froeyen, Boris Pastorino, Marijke M F Alen, Juan A. Mondotte, Piet Herdewijn, Michael Jacobs, Xavier De Lamballerie, Dominique Schols, Andrea V. Gamarnik, F. Sztaricskai, Johan Neyts

Research output: Contribution to journalArticle

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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 [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 yellow fever virus 17D (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 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.

Original languageEnglish
Pages (from-to)5269-5280
Number of pages12
JournalAntimicrobial Agents and Chemotherapy
Volume54
Issue number12
DOIs
Publication statusPublished - Dec 2010

Fingerprint

Yellow fever virus
Dengue Virus
Dengue
Virus Replication
Doxorubicin
Anti-Bacterial Agents
Renilla Luciferases
Viruses
Virus Attachment
Flavivirus
Virus Internalization
Replicon
Ribavirin
Viral RNA
Cytostatic Agents
Reverse Transcriptase Polymerase Chain Reaction
Nucleosides
In Vitro Techniques
Esters
Carbohydrates

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

Cite this

Kaptein, S. J. F., De Burghgraeve, T., Froeyen, M., Pastorino, B., Alen, M. M. F., Mondotte, J. A., ... Neyts, J. (2010). A derivate of the antibiotic doxorubicin is a selective inhibitor of dengue and yellow fever virus replication in vitro. Antimicrobial Agents and Chemotherapy, 54(12), 5269-5280. https://doi.org/10.1128/AAC.00686-10

A derivate of the antibiotic doxorubicin is a selective inhibitor of dengue and yellow fever virus replication in vitro. / 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, F.; Neyts, Johan.

In: Antimicrobial Agents and Chemotherapy, Vol. 54, No. 12, 12.2010, p. 5269-5280.

Research output: Contribution to journalArticle

Kaptein, SJF, De Burghgraeve, T, Froeyen, M, Pastorino, B, Alen, MMF, Mondotte, JA, Herdewijn, P, Jacobs, M, De Lamballerie, X, Schols, D, Gamarnik, AV, Sztaricskai, F & Neyts, J 2010, 'A derivate of the antibiotic doxorubicin is a selective inhibitor of dengue and yellow fever virus replication in vitro', Antimicrobial Agents and Chemotherapy, vol. 54, no. 12, pp. 5269-5280. https://doi.org/10.1128/AAC.00686-10
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, F. ; Neyts, Johan. / A derivate of the antibiotic doxorubicin is a selective inhibitor of dengue and yellow fever virus replication in vitro. In: Antimicrobial Agents and Chemotherapy. 2010 ; Vol. 54, No. 12. pp. 5269-5280.
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