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Front Immunol. 2019 Jan 29;10:60. doi: 10.3389/fimmu.2019.00060. eCollection 2019.

Repurposing of Drugs as Novel Influenza Inhibitors From Clinical Gene Expression Infection Signatures.

Author information

1
Virologie et Pathologie Humaine-VirPath Team, Centre International de Recherche en Infectiologie, INSERM U1111, CNRS UMR5308, ENS Lyon, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France.
2
Research Center in Infectious Diseases of the CHU de Quebec and Laval University, Quebec City, QC, Canada.
3
Viroscan3D SAS, Lyon, France.
4
VirNext, Faculté de Médecine RTH Laennec, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France.
5
ProfileXpert, SFR-Est, CNRS UMR-S3453, INSERM US7, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France.
6
Laboratoire de Virologie, Centre National de Référence des virus Influenza Sud, Institut des Agents Infectieux, Groupement Hospitalier Nord, Hospices Civils de Lyon, Lyon, France.
7
Pôle de Réanimation, Hôpital Roger Salengro, Centre Hospitalier Régional et Universitaire de Lille, Université de Lille 2, Lille, France.
8
Ecologie Microbienne, UMR CNRS 5557, USC INRA 1364, Université Claude Bernard Lyon 1, Université de Lyon, Villeurbanne, France.
9
Service d'Anesthésie et de Réanimation, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France.
10
Pathophysiology of Injury-Induced Immunosuppression (PI3), EA 7426 Hospices Civils de Lyon, bioMérieux, Université Claude Bernard Lyon 1, Hôpital Edouard Herriot, Lyon, France.

Abstract

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. 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. 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. 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.

KEYWORDS:

antivirals; drug repurposing; host targeting; influenza viruses; inhibitors of viral infection; transcriptome

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