Synergistic drug combination effectively blocks Ebola virus infection

Wei Sun; Shihua He; Carles Martínez-Romero; Jennifer Kouznetsova; Gregory Tawa; Miao Xu; Paul Shinn; Ethan G. Fisher; Yan Long; Omid Motabar; Shu Yang; Philip E. Sanderson; Peter R. Williamson; Adolfo García-Sastre; Xiangguo Qiu; Wei Zheng

doi:10.1016/j.antiviral.2016.11.017

Synergistic drug combination effectively blocks Ebola virus infection

Wei Sun, Shihua He, Carles Martínez-Romero, Jennifer Kouznetsova, Gregory Tawa, Miao Xu, Paul Shinn, Ethan G. Fisher, Yan Long, Omid Motabar, Shu Yang, Philip E. Sanderson, Peter R. Williamson, Adolfo García-Sastre, Xiangguo Qiu, Wei Zheng

Research output: Contribution to journal › Article › peer-review

73 Scopus citations

Abstract

Although a group of FDA-approved drugs were previously identified with activity against Ebola virus (EBOV), most of them are not clinically useful because their human blood concentrations are not high enough to inhibit EBOV infection. We screened 795 unique three-drug combinations in an EBOV entry assay. Two sets of three-drug combinations, toremifene-mefloquine-posaconazole and toremifene-clarithromycin-posaconazole, were identified that effectively blocked EBOV entry and were further validated for inhibition of live EBOV infection. The individual drug concentrations in the combinations were reduced to clinically relevant levels. We identified mechanisms of action of these drugs: functional inhibitions of Niemann–Pick C1, acid sphingomyelinase, and lysosomal calcium release. Our findings identify the drug combinations with potential to treat EBOV infection.

Original language	English
Pages (from-to)	165-172
Number of pages	8
Journal	Antiviral Research
Volume	137
DOIs	https://doi.org/10.1016/j.antiviral.2016.11.017
State	Published - 1 Jan 2017

Keywords

Drug combination
Drug repurposing
Ebola prevention
Ebola treatment
Polypharmacology

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Sun, W., He, S., Martínez-Romero, C., Kouznetsova, J., Tawa, G., Xu, M., Shinn, P., Fisher, E. G., Long, Y., Motabar, O., Yang, S., Sanderson, P. E., Williamson, P. R., García-Sastre, A., Qiu, X., & Zheng, W. (2017). Synergistic drug combination effectively blocks Ebola virus infection. Antiviral Research, 137, 165-172. https://doi.org/10.1016/j.antiviral.2016.11.017

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abstract = "Although a group of FDA-approved drugs were previously identified with activity against Ebola virus (EBOV), most of them are not clinically useful because their human blood concentrations are not high enough to inhibit EBOV infection. We screened 795 unique three-drug combinations in an EBOV entry assay. Two sets of three-drug combinations, toremifene-mefloquine-posaconazole and toremifene-clarithromycin-posaconazole, were identified that effectively blocked EBOV entry and were further validated for inhibition of live EBOV infection. The individual drug concentrations in the combinations were reduced to clinically relevant levels. We identified mechanisms of action of these drugs: functional inhibitions of Niemann–Pick C1, acid sphingomyelinase, and lysosomal calcium release. Our findings identify the drug combinations with potential to treat EBOV infection.",

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author = "Wei Sun and Shihua He and Carles Mart{\'i}nez-Romero and Jennifer Kouznetsova and Gregory Tawa and Miao Xu and Paul Shinn and Fisher, {Ethan G.} and Yan Long and Omid Motabar and Shu Yang and Sanderson, {Philip E.} and Williamson, {Peter R.} and Adolfo Garc{\'i}a-Sastre and Xiangguo Qiu and Wei Zheng",

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AU - Xu, Miao

AU - Shinn, Paul

AU - Fisher, Ethan G.

AU - Long, Yan

AU - Motabar, Omid

AU - Yang, Shu

AU - Sanderson, Philip E.

AU - Williamson, Peter R.

AU - García-Sastre, Adolfo

AU - Qiu, Xiangguo

AU - Zheng, Wei

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AB - Although a group of FDA-approved drugs were previously identified with activity against Ebola virus (EBOV), most of them are not clinically useful because their human blood concentrations are not high enough to inhibit EBOV infection. We screened 795 unique three-drug combinations in an EBOV entry assay. Two sets of three-drug combinations, toremifene-mefloquine-posaconazole and toremifene-clarithromycin-posaconazole, were identified that effectively blocked EBOV entry and were further validated for inhibition of live EBOV infection. The individual drug concentrations in the combinations were reduced to clinically relevant levels. We identified mechanisms of action of these drugs: functional inhibitions of Niemann–Pick C1, acid sphingomyelinase, and lysosomal calcium release. Our findings identify the drug combinations with potential to treat EBOV infection.

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Synergistic drug combination effectively blocks Ebola virus infection

Abstract

Keywords

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