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Repurposing of drugs as novel influenza inhibitors from clinical gene expression infection signatures

View ORCID ProfileAndrés Pizzorno, View ORCID ProfileOlivier Terrier, Claire Nicolas de Lamballerie, Thomas Julien, Blandine Padey, Aurélien Traversier, Magali Roche, Marie-Eve Hamelin, Chantal Rhéaume, Séverine Croze, Vanessa Escuret, Julien Poissy, Bruno Lina, Catherine Legras-Lachuer, Julien Textoris, Guy Boivin, Manuel Rosa-Calatrava
doi: https://doi.org/10.1101/401315
Andrés Pizzorno
1Virologie et Pathologie Humaine - VirPath team, Centre International de Recherche en Infectiologie (CIRI), INSERM U1111, CNRS UMR5308, ENS Lyon, Université Claude Bernard Lyon 1, Université de Lyon, Lyon 69008, France
2Research Center in Infectious Diseases of the CHU de Quebec and Laval University, Quebec City, QC G1V 4G2, Canada
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  • ORCID record for Andrés Pizzorno
Olivier Terrier
1Virologie et Pathologie Humaine - VirPath team, Centre International de Recherche en Infectiologie (CIRI), INSERM U1111, CNRS UMR5308, ENS Lyon, Université Claude Bernard Lyon 1, Université de Lyon, Lyon 69008, France
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  • For correspondence: olivier.terrier@univ-lyon1.fr manuel.rosa-calatrava@univ-lyon1.fr
Claire Nicolas de Lamballerie
1Virologie et Pathologie Humaine - VirPath team, Centre International de Recherche en Infectiologie (CIRI), INSERM U1111, CNRS UMR5308, ENS Lyon, Université Claude Bernard Lyon 1, Université de Lyon, Lyon 69008, France
3Viroscan3D SAS, Lyon 69008, France
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Thomas Julien
1Virologie et Pathologie Humaine - VirPath team, Centre International de Recherche en Infectiologie (CIRI), INSERM U1111, CNRS UMR5308, ENS Lyon, Université Claude Bernard Lyon 1, Université de Lyon, Lyon 69008, France
4VirNext, Faculté de Médecine RTH Laennec, Université Claude Bernard Lyon 1, Université de Lyon, Lyon 69008, France
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Blandine Padey
1Virologie et Pathologie Humaine - VirPath team, Centre International de Recherche en Infectiologie (CIRI), INSERM U1111, CNRS UMR5308, ENS Lyon, Université Claude Bernard Lyon 1, Université de Lyon, Lyon 69008, France
4VirNext, Faculté de Médecine RTH Laennec, Université Claude Bernard Lyon 1, Université de Lyon, Lyon 69008, France
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Aurélien Traversier
1Virologie et Pathologie Humaine - VirPath team, Centre International de Recherche en Infectiologie (CIRI), INSERM U1111, CNRS UMR5308, ENS Lyon, Université Claude Bernard Lyon 1, Université de Lyon, Lyon 69008, France
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Magali Roche
3Viroscan3D SAS, Lyon 69008, France
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Marie-Eve Hamelin
2Research Center in Infectious Diseases of the CHU de Quebec and Laval University, Quebec City, QC G1V 4G2, Canada
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Chantal Rhéaume
2Research Center in Infectious Diseases of the CHU de Quebec and Laval University, Quebec City, QC G1V 4G2, Canada
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Séverine Croze
5ProfileXpert, SFR-Est, CNRS UMR-S3453, INSERM US7, Université Claude Bernard Lyon 1, Université de Lyon, Lyon 69008, France
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Vanessa Escuret
1Virologie et Pathologie Humaine - VirPath team, Centre International de Recherche en Infectiologie (CIRI), INSERM U1111, CNRS UMR5308, ENS Lyon, Université Claude Bernard Lyon 1, Université de Lyon, Lyon 69008, France
6Laboratoire de Virologie, Centre National de Référence des virus Influenza Sud, Institut desAgents Infectieux, Groupement Hospitalier Nord, Hospices Civils de Lyon, Lyon F-21 France
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Julien Poissy
7Pôle de Réanimation, Hôpital Roger Salengro, Centre Hospitalier Régional 22 et Universitaire de Lille, Université de Lille 2, Lille 59000, France
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Bruno Lina
1Virologie et Pathologie Humaine - VirPath team, Centre International de Recherche en Infectiologie (CIRI), INSERM U1111, CNRS UMR5308, ENS Lyon, Université Claude Bernard Lyon 1, Université de Lyon, Lyon 69008, France
6Laboratoire de Virologie, Centre National de Référence des virus Influenza Sud, Institut desAgents Infectieux, Groupement Hospitalier Nord, Hospices Civils de Lyon, Lyon F-21 France
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Catherine Legras-Lachuer
3Viroscan3D SAS, Lyon 69008, France
8Ecologie Microbienne, UMR CNRS 5557, USC INRA 1364, Université Claude Bernard Lyon 1, Université de Lyon, Villeurbanne 69100, France
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Julien Textoris
9Service d’Anesthésie et de Réanimation, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon 69003, France
10Pathophysiology of Injury-Induced Immunosuppression (PI3), EA 7426 Hospices Civils de Lyon,bioMérieux, Université Claude Bernard Lyon 1, Hôpital Edouard Herriot, Lyon 69003, France
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Guy Boivin
2Research Center in Infectious Diseases of the CHU de Quebec and Laval University, Quebec City, QC G1V 4G2, Canada
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Manuel Rosa-Calatrava
1Virologie et Pathologie Humaine - VirPath team, Centre International de Recherche en Infectiologie (CIRI), INSERM U1111, CNRS UMR5308, ENS Lyon, Université Claude Bernard Lyon 1, Université de Lyon, Lyon 69008, France
3Viroscan3D SAS, Lyon 69008, France
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  • For correspondence: olivier.terrier@univ-lyon1.fr manuel.rosa-calatrava@univ-lyon1.fr
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Abstract

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.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted August 27, 2018.
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Repurposing of drugs as novel influenza inhibitors from clinical gene expression infection signatures
Andrés Pizzorno, Olivier Terrier, Claire Nicolas de Lamballerie, Thomas Julien, Blandine Padey, Aurélien Traversier, Magali Roche, Marie-Eve Hamelin, Chantal Rhéaume, Séverine Croze, Vanessa Escuret, Julien Poissy, Bruno Lina, Catherine Legras-Lachuer, Julien Textoris, Guy Boivin, Manuel Rosa-Calatrava
bioRxiv 401315; doi: https://doi.org/10.1101/401315
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Repurposing of drugs as novel influenza inhibitors from clinical gene expression infection signatures
Andrés Pizzorno, Olivier Terrier, Claire Nicolas de Lamballerie, Thomas Julien, Blandine Padey, Aurélien Traversier, Magali Roche, Marie-Eve Hamelin, Chantal Rhéaume, Séverine Croze, Vanessa Escuret, Julien Poissy, Bruno Lina, Catherine Legras-Lachuer, Julien Textoris, Guy Boivin, Manuel Rosa-Calatrava
bioRxiv 401315; doi: https://doi.org/10.1101/401315

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