title: A human genome-wide loss-of-function screen identifies effective chikungunya antiviral drugs.
abstract: Chikungunya virus (CHIKV) is a globally spreading alphavirus against which there is no commercially available vaccine or therapy. Here we use a genome-wide siRNA screen to identify 156 proviral and 41 antiviral host factors affecting CHIKV replication. We analyse the cellular pathways in which human proviral genes are involved and identify druggable targets. Twenty-one small-molecule inhibitors, some of which are FDA approved, targeting six proviral factors or pathways, have high antiviral activity in vitro, with low toxicity. Three identified inhibitors have prophylactic antiviral effects in mouse models of chikungunya infection. Two of them, the calmodulin inhibitor pimozide and the fatty acid synthesis inhibitor TOFA, have a therapeutic effect in vivo when combined. These results demonstrate the value of loss-of-function screening and pathway analysis for the rational identification of small molecules with therapeutic potential and pave the way for the development of new, host-directed, antiviral agents.
authors.affiliation: Max Planck Institute for Infection Biology, Department of Molecular Biology, Charitéplatz 1, 10117 Berlin, Germany.|Steinbeis Innovation gGmbH, Center for Systems Biomedicine, Haydnallee 21, 14612 Falkensee, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Karlas
authors.affiliation: Institut Pasteur, Biology of Infection Unit, 28 rue du Dr. Roux, 75015 Paris, France.|Inserm U1117, 28 rue du Dr. Roux, 75015 Paris, France.
authors.forename: Stefano
authors.initials: S
authors.lastname: Berre
authors.affiliation: Institut Pasteur, Biology of Infection Unit, 28 rue du Dr. Roux, 75015 Paris, France.|Inserm U1117, 28 rue du Dr. Roux, 75015 Paris, France.
authors.forename: Thérèse
authors.initials: T
authors.lastname: Couderc
authors.affiliation: Institute of Technology, University of Tartu, Nooruse 1, 50411 Tartu, Estonia.
authors.forename: Margus
authors.initials: M
authors.lastname: Varjak
authors.affiliation: Max Planck Institute for Infection Biology, Department of Molecular Biology, Charitéplatz 1, 10117 Berlin, Germany.|Steinbeis Innovation gGmbH, Center for Systems Biomedicine, Haydnallee 21, 14612 Falkensee, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Braun
authors.affiliation: Steinbeis Innovation gGmbH, Center for Systems Biomedicine, Haydnallee 21, 14612 Falkensee, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Meyer
authors.affiliation: Institut Pasteur, Biology of Infection Unit, 28 rue du Dr. Roux, 75015 Paris, France.|Inserm U1117, 28 rue du Dr. Roux, 75015 Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gangneux
authors.affiliation: Institute of Technology, University of Tartu, Nooruse 1, 50411 Tartu, Estonia.
authors.forename: Liis
authors.initials: L
authors.lastname: Karo-Astover
authors.affiliation: Max Planck Institute for Infection Biology, Department of Molecular Biology, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Friderike
authors.initials: F
authors.lastname: Weege
authors.affiliation: Institute of Virology, Charité University Medicine, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Raftery
authors.affiliation: Institute of Virology, Charité University Medicine, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Günther
authors.initials: G
authors.lastname: Schönrich
authors.affiliation: Max Planck Institute for Infection Biology, Core Facility Experimental Animals, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Klemm
authors.affiliation: Ludwig-Maximilians-University, Department of Pharmacy-Center for Drug Research, Butenandtstraße 5-13, 81377 Munich, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Wurzlbauer
authors.affiliation: Ludwig-Maximilians-University, Department of Pharmacy-Center for Drug Research, Butenandtstraße 5-13, 81377 Munich, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Bracher
authors.affiliation: Institute of Technology, University of Tartu, Nooruse 1, 50411 Tartu, Estonia.
authors.forename: Andres
authors.initials: A
authors.lastname: Merits
authors.affiliation: Max Planck Institute for Infection Biology, Department of Molecular Biology, Charitéplatz 1, 10117 Berlin, Germany.|Steinbeis Innovation gGmbH, Center for Systems Biomedicine, Haydnallee 21, 14612 Falkensee, Germany.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Meyer
authors.affiliation: Institut Pasteur, Biology of Infection Unit, 28 rue du Dr. Roux, 75015 Paris, France.|Inserm U1117, 28 rue du Dr. Roux, 75015 Paris, France.|Paris Descartes University, Sorbonne Paris Cité, Division of Infectious Diseases and Tropical Medicine, Necker-Enfants Malades University Hospital, Institut Imagine, 149, rue de Sèvres 75743 Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Lecuit
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D065632:Chikungunya Fever / Q000235:genetics / Q000517:prevention & control / Q000821:virology; D002646:Chikungunya virus / Q000235:genetics* / Q000502:physiology; D005663:Furans / Q000494:pharmacology; D020869:Gene Expression Profiling / Q000379:methods; D015894:Genome, Human / Q000235:genetics*; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D051379:Mice; D010868:Pimozide / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics*; D054852:Small Molecule Libraries / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects* / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D005663:Furans; D034741:RNA, Small Interfering; D054852:Small Molecule Libraries; D010868:Pimozide; C014289:5-(tetradecyloxy)-2-furancarboxylic acid