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

2016; Nature Portfolio; Volume: 7; Issue: 1 Linguagem: Inglês

10.1038/ncomms11320

2041-1723

Alexander Karlas, Stefano Berrè, Thérèse Couderc, Margus Varjak, Peter Braun, Michaël Meyer, Nicolas Gangneux, Liis Karo-Astover, Friderike Weege, Martin Raftery, Günther Schönrich, Uwe Klemm, Anne Wurzlbauer, Franz Bracher, Andres Merits, Thomas F. Meyer, Marc Lecuit,

interferon and immune responses

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.