title: The natural compound silvestrol is a potent inhibitor of Ebola virus replication.
abstract: The DEAD-box RNA helicase eIF4A, which is part of the heterotrimeric translation initiation complex in eukaryotes, is an important novel drug target in cancer research because its helicase activity is required to unwind extended and highly structured 5'-UTRs of several proto-oncogenes. Silvestrol, a natural compound isolated from the plant Aglaia foveolata, is a highly efficient, non-toxic and specific inhibitor of eIF4A. Importantly, 5'-capped viral mRNAs often contain structured 5'-UTRs as well, which may suggest a dependence on eIF4A for their translation by the host protein synthesis machinery. In view of the recent Ebola virus (EBOV) outbreak in West Africa, the identification of potent antiviral compounds is urgently required. Since Ebola mRNAs are 5'-capped and harbor RNA secondary structures in their extended 5'-UTRs, we initiated a BSL4 study to analyze silvestrol in EBOV-infected Huh-7 cells and in primary human macrophages for its antiviral activity. We observed that silvestrol inhibits EBOV infection at low nanomolar concentrations, as inferred from large reductions of viral titers. This correlated with an almost complete disappearance of EBOV proteins, comparable in effect to the translational shutdown of expression of the proto-oncoprotein PIM1, a cellular kinase known to be affected by silvestrol. Effective silvestrol concentrations were non-toxic in the tested cell systems. Thus, silvestrol appears to be a promising first-line drug for the treatment of acute EBOV and possibly other viral infections.
authors.affiliation: Institut für Virologie, Philipps-Universität Marburg, Hans-Meerwein-Str. 2, 35043, Marburg, Germany; Deutsches Zentrum für Infektionsforschung (DZIF) at the Partner Site Gießen-Marburg-Langen, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Biedenkopf
authors.affiliation: Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35037, Marburg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Lange-Grünweller
authors.affiliation: Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35037, Marburg, Germany.
authors.forename: Falk W
authors.initials: FW
authors.lastname: Schulte
authors.affiliation: Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35037, Marburg, Germany.
authors.forename: Aileen
authors.initials: A
authors.lastname: Weißer
authors.affiliation: Institut für Medizinische Virologie, Justus-Liebig-Universität Gießen, Schubertstraße 81, 35392, Gießen, Germany; Deutsches Zentrum für Infektionsforschung (DZIF) at the Partner Site Gießen-Marburg-Langen, Germany.
authors.forename: Christin
authors.initials: C
authors.lastname: Müller
authors.affiliation: Institut für Virologie, Philipps-Universität Marburg, Hans-Meerwein-Str. 2, 35043, Marburg, Germany; Deutsches Zentrum für Infektionsforschung (DZIF) at the Partner Site Gießen-Marburg-Langen, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Becker
authors.affiliation: Institut für Virologie, Philipps-Universität Marburg, Hans-Meerwein-Str. 2, 35043, Marburg, Germany; Deutsches Zentrum für Infektionsforschung (DZIF) at the Partner Site Gießen-Marburg-Langen, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Becker
authors.affiliation: Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35037, Marburg, Germany.
authors.forename: Roland K
authors.initials: RK
authors.lastname: Hartmann
authors.affiliation: Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35037, Marburg, Germany. Electronic address: gruenwel@staff.uni-marburg.de.
authors.forename: Arnold
authors.initials: A
authors.lastname: Grünweller
mesh_terms: D020121:5' Untranslated Regions / Q000187:drug effects; D000354:Africa, Western / Q000453:epidemiology; D000998:Antiviral Agents / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D055808:Drug Discovery; D029043:Ebolavirus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D019142:Hemorrhagic Fever, Ebola / Q000188:drug therapy / Q000453:epidemiology; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000821:virology*; D010442:Peptide Chain Initiation, Translational / Q000187:drug effects; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism; D012315:RNA Caps / Q000235:genetics / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology* / Q000633:toxicity; D014779:Virus Replication / Q000187:drug effects*; D001572:Benzofurans
chemical_list: D020121:5' Untranslated Regions; D000998:Antiviral Agents; D051573:Proto-Oncogene Proteins c-pim-1; D012315:RNA Caps; D014315:Triterpenes; C489897:silvestrol; D001572:Benzofurans; C496634:PIM1 protein, human
keywords: Ebola; PIM1; Primary macrophages; Silvestrol; Translation inhibition; eIF4A helicase