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.
Type de document :
Article dans une revue
Nature Communications, Nature Publishing Group, 2016, 7, pp.11320. 〈10.1038/ncomms11320〉
Liste complète des métadonnées

Littérature citée [50 références]  Voir  Masquer  Télécharger

https://hal-pasteur.archives-ouvertes.fr/pasteur-01515939
Contributeur : Marie-Claire Rozier <>
Soumis le : vendredi 28 avril 2017 - 12:11:40
Dernière modification le : mercredi 3 octobre 2018 - 14:52:02
Document(s) archivé(s) le : samedi 29 juillet 2017 - 13:18:18

Fichier

ncomms11320.pdf
Publication financée par une institution

Licence


Distributed under a Creative Commons Paternité 4.0 International License

Identifiants

Collections

Citation

Alexander Karlas, Stefano Berre, Thérèse Couderc, Margus Varjak, Peter Braun, et al.. A human genome-wide loss-of-function screen identifies effective chikungunya antiviral drugs.. Nature Communications, Nature Publishing Group, 2016, 7, pp.11320. 〈10.1038/ncomms11320〉. 〈pasteur-01515939〉

Partager

Métriques

Consultations de la notice

358

Téléchargements de fichiers

164