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

Karlas, A. et al. (2016) A human genome-wide loss-of-function screen identifies effective chikungunya antiviral drugs. Nature Communications, 7, p. 11320. (PMID:27177310) (PMCID:PMC4865845)

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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.

Item Type:Articles
Additional Information:This project was funded in part by the EU project FP7-ICRES (grant no. 261202), and LabEx IBEID, Institut Pasteur and Inserm. S.B. was funded by the Pasteur-Roux fellowship.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Varjak, Dr Margus
Authors: Karlas, A., Berre, S., Couderc, T., Varjak, M., Braun, P., Meyer, M., Gangneux, N., Karo-Astover, L., Weege, F., Raftery, M., Schönrich, G., Klemm, U., Wurzlbauer, A., Bracher, F., Merits, A., Meyer, T. F., and Lecuit, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Nature Communications
Publisher:Nature Publishing Group
ISSN:2041-1723
ISSN (Online):2041-1723
Published Online:12 May 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Nature Communications 7:11320
Publisher Policy:Reproduced under a Creative Commons License

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