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Antiviral Res. 2017 Jan;137:165-172. doi: 10.1016/j.antiviral.2016.11.017. Epub 2016 Nov 24.

Synergistic drug combination effectively blocks Ebola virus infection.

Author information

1
National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda MD 20892, USA.
2
Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba R3E 3R2, Canada.
3
Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada.
4
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
5
Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
6
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
7
Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
#
Contributed equally

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.

KEYWORDS:

Drug combination; Drug repurposing; Ebola prevention; Ebola treatment; Polypharmacology

PMID:
27890675
PMCID:
PMC5182099
DOI:
10.1016/j.antiviral.2016.11.017
[Indexed for MEDLINE]
Free PMC Article

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