title: Synergistic drug combination effectively blocks Ebola virus infection.
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.
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda MD 20892, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba R3E 3R2, Canada.|Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada.
authors.forename: Shihua
authors.initials: S
authors.lastname: He
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Carles
authors.initials: C
authors.lastname: Martínez-Romero
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda MD 20892, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kouznetsova
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda MD 20892, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Tawa
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda MD 20892, USA.
authors.forename: Miao
authors.initials: M
authors.lastname: Xu
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda MD 20892, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Shinn
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda MD 20892, USA.
authors.forename: Ethan
authors.initials: E
authors.lastname: Fisher
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda MD 20892, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Long
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda MD 20892, USA.
authors.forename: Omid
authors.initials: O
authors.lastname: Motabar
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda MD 20892, USA.
authors.forename: Shu
authors.initials: S
authors.lastname: Yang
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda MD 20892, USA.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Sanderson
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Williamson
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
authors.affiliation: Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba R3E 3R2, Canada.|Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada.
authors.forename: Xiangguo
authors.initials: X
authors.lastname: Qiu
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda MD 20892, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D002522:Chlorocebus aethiops; D017291:Clarithromycin / Q000494:pharmacology; D004338:Drug Combinations; D004357:Drug Synergism; D029043:Ebolavirus / Q000187:drug effects*; D019142:Hemorrhagic Fever, Ebola / Q000188:drug therapy / Q000821:virology; D057166:High-Throughput Screening Assays; D006801:Humans; D015767:Mefloquine / Q000494:pharmacology; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors / Q000187:drug effects; D017312:Toremifene / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014709:Vero Cells; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D004338:Drug Combinations; D014230:Triazoles; C101425:posaconazole; D017312:Toremifene; C112980:acid sphingomyelinase-1; D013108:Sphingomyelin Phosphodiesterase; D017291:Clarithromycin; D015767:Mefloquine
keywords: Drug combination; Drug repurposing; Ebola prevention; Ebola treatment; Polypharmacology