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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.
Pizzorno A1,2, Terrier O1, Nicolas de Lamballerie C1,3, Julien T1,4, Padey B1,4, Traversier A1, Roche M3, Hamelin ME2, Rh?aume C2, Croze S5, Escuret V1,6, Poissy J7, Lina B1,6, Legras-Lachuer C3,8, Textoris J9,10, Boivin G2, Rosa-Calatrava M1,4.
Author information
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
PMID: 30761132 PMCID: PMC6361841 DOI: 10.3389/fimmu.2019.00060
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Repurposing of Drugs as Novel Influenza Inhibitors From Clinical Gene Expression Infection Signatures.
Pizzorno A1,2, Terrier O1, Nicolas de Lamballerie C1,3, Julien T1,4, Padey B1,4, Traversier A1, Roche M3, Hamelin ME2, Rh?aume C2, Croze S5, Escuret V1,6, Poissy J7, Lina B1,6, Legras-Lachuer C3,8, Textoris J9,10, Boivin G2, Rosa-Calatrava M1,4.
Author information
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
PMID: 30761132 PMCID: PMC6361841 DOI: 10.3389/fimmu.2019.00060
Free full text