A human genome-wide loss-of-function screen identifies effective chikungunya antiviral drugs

Alexander Karlas, Stefano Berre, Thérèse Couderc, Margus Varjak, Peter Braun, Michael Meyer, Nicolas Gangneux, Liis Karo-Astover, Friderike Weege, Martin Raftery, Günther Schönrich, Uwe Klemm, Anne Wurzlbauer, Franz Bracher, Andres Merits, Thomas F. Meyer () and Marc Lecuit ()
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Alexander Karlas: Max Planck Institute for Infection Biology
Stefano Berre: Institut Pasteur, Biology of Infection Unit
Thérèse Couderc: Institut Pasteur, Biology of Infection Unit
Margus Varjak: Institute of Technology, University of Tartu
Peter Braun: Max Planck Institute for Infection Biology
Michael Meyer: Steinbeis Innovation gGmbH, Center for Systems Biomedicine
Nicolas Gangneux: Institut Pasteur, Biology of Infection Unit
Liis Karo-Astover: Institute of Technology, University of Tartu
Friderike Weege: Max Planck Institute for Infection Biology
Martin Raftery: Institute of Virology, Charité University Medicine
Günther Schönrich: Institute of Virology, Charité University Medicine
Uwe Klemm: Max Planck Institute for Infection Biology, Core Facility Experimental Animals
Anne Wurzlbauer: Ludwig-Maximilians-University
Franz Bracher: Ludwig-Maximilians-University
Andres Merits: Institute of Technology, University of Tartu
Thomas F. Meyer: Max Planck Institute for Infection Biology
Marc Lecuit: Institut Pasteur, Biology of Infection Unit

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11320

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