PT  - JOURNAL ARTICLE
AU  - Andrés Pizzorno
AU  - Olivier Terrier
AU  - Claire Nicolas de Lamballerie
AU  - Thomas Julien
AU  - Blandine Padey
AU  - Aurélien Traversier
AU  - Magali Roche
AU  - Marie-Eve Hamelin
AU  - Chantal Rhéaume
AU  - Séverine Croze
AU  - Vanessa Escuret
AU  - Julien Poissy
AU  - Bruno Lina
AU  - Catherine Legras-Lachuer
AU  - Julien Textoris
AU  - Guy Boivin
AU  - Manuel Rosa-Calatrava
TI  - Repurposing of drugs as novel influenza inhibitors from clinical gene expression infection signatures
AID  - 10.1101/401315
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 401315
4099  - http://biorxiv.org/content/early/2018/08/27/401315.short
4100  - http://biorxiv.org/content/early/2018/08/27/401315.full
AB  - Background: Influenza virus infections remain a major and recurrent public health burden. The intrinsic ever-evolving nature of this virus, the suboptimal efficacy of current influenza inactivated vaccines, as well as the emergence of resistance against a limited antiviral arsenal, highlight the critical need for novel therapeutic approaches. In this context, the aim of this study was to develop and validate an innovative strategy for drug repurposing as host-targeted inhibitors of influenza viruses and the rapid evaluation of the most promising candidates in Phase II clinical trials.Methods: We exploited in vivo global transcriptomic signatures of infection directly obtained from a patient cohort to determine a shortlist of already marketed drugs with newly identified, host-targeted inhibitory properties against influenza virus. The antiviral potential of selected repurposing candidates was further evaluated in vitro, in vivo and ex vivo.Results: Our strategy allowed the selection of a shortlist of 35 high potential candidates out of a rationalized computational screening of 1,309 FDA-approved bioactive molecules, 31 of which were validated for their significant in vitro antiviral activity. Our in vivo and ex vivo results highlight diltiazem, a calcium channel blocker currently used in the treatment of hypertension, as a promising option for the treatment of influenza infections. Additionally, transcriptomic signature analysis further revealed the so far undescribed capacity of diltiazem to modulate the expression of specific genes related to the host antiviral response and cholesterol metabolism. Finally, combination treatment with diltiazem and virus-targeted oseltamivir neuraminidase inhibitor further increased antiviral efficacy, prompting rapid authorization for the initiation of a Phase II clinical trial.Conclusions: This original, host-targeted, drug repurposing strategy constitutes an effective and highly reactive process for the rapid identification of novel anti-infectious drugs, with potential major implications for the management of antimicrobial resistance and the rapid response to future epidemic or pandemic (re)emerging diseases for which we are still disarmed.