Repurposing of Drugs as Novel Influenza Inhibitors From Clinical Gene Expression Infection Signatures - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Frontiers in Immunology Année : 2019

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

Magali Roche
  • Fonction : Auteur
  • PersonId : 783041
  • IdRef : 180877682
Séverine Croze
  • Fonction : Auteur
Julien Poissy
Julien Textoris

Résumé

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

Domaines

Virologie
Fichier principal
Vignette du fichier
Pizzorno, Terrier Frontiers in Immunology 2019.pdf (2.89 Mo) Télécharger le fichier
Origine : Fichiers éditeurs autorisés sur une archive ouverte
Loading...

Dates et versions

hal-02322394 , version 1 (21-10-2019)

Identifiants

Citer

Andres Pizzorno, Olivier Terrier, Claire Nicolas de Lamballerie, Thomas Julien, Blandine Padey, et al.. Repurposing of Drugs as Novel Influenza Inhibitors From Clinical Gene Expression Infection Signatures. Frontiers in Immunology, 2019, 10, ⟨10.3389/fimmu.2019.00060⟩. ⟨hal-02322394⟩
75 Consultations
58 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More