La modulation de la signature transcriptomique de l’hôte infecté : une nouvelle stratégie thérapeutique dans les viroses graves ? Exemple de la grippe

Poissy, Julien; Terrier, B.; Lina, Bruno; Textoris, Julien; Rosa‐Calatrava, Manuel

doi:10.1007/s13546-016-1188-1

Cited by 3 publications

(1 citation statement)

References 62 publications

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“…The existing urge for alternative strategies to cope with the limited efficacy of currently approved antivirals for the prevention and treatment of influenza infections (2, 41, 42), mostly in the case of patients with severe influenza and acute respiratory distress syndrome (ARDS) (43, 44), represented the central driving force of this study. Here, we developed and validated for the first time an innovative approach based on clinical genomic signatures of respiratory viral infections for the rapid discovery, in vitro, in vivo , and ex-vivo evaluation, as well as the repurposing of FDA-approved drugs for their newly identified host-targeted inhibitory and protective properties against influenza infections.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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Séquençage à haut débit pour le diagnostic en maladies infectieuses : exemple de la métagénomique shotgun dans les infections du système nerveux central

Marchand

Rodriguez

Woerther

2024

La Revue de Médecine Interne

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

Pizzorno

Terrier

Lamballerie

et al. 2018

Preprint

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42Background: Influenza virus infections remain a major and recurrent public health burden. The 43 intrinsic ever-evolving nature of this virus, the suboptimal efficacy of current influenza 44 inactivated vaccines, as well as the emergence of resistance against a limited antiviral arsenal, 45 highlight the critical need for novel therapeutic approaches. In this context, the aim of this study 46 was to develop and validate an innovative strategy for drug repurposing as host-targeted 47 inhibitors of influenza viruses and the rapid evaluation of the most promising candidates in Phase 48 II clinical trials. 49 Methods:We exploited in vivo global transcriptomic signatures of infection directly obtained 50 from a patient cohort to determine a shortlist of already marketed drugs with newly identified, 51 host-targeted inhibitory properties against influenza virus. The antiviral potential of selected 52 repurposing candidates was further evaluated in vitro, in vivo and ex vivo. 53 Results: Our strategy allowed the selection of a shortlist of 35 high potential candidates out of a 54 rationalized computational screening of 1,309 FDA-approved bioactive molecules, 31 of which 55 were validated for their significant in vitro antiviral activity. Our in vivo and ex vivo results 56 highlight diltiazem, a calcium channel blocker currently used in the treatment of hypertension, as 57 a promising option for the treatment of influenza infections. Additionally, transcriptomic 58 signature analysis further revealed the so far undescribed capacity of diltiazem to modulate the 59 expression of specific genes related to the host antiviral response and cholesterol metabolism.60 Finally, combination treatment with diltiazem and virus-targeted oseltamivir neuraminidase 61 inhibitor further increased antiviral efficacy, prompting rapid authorization for the initiation of a 62 Phase II clinical trial. 63 4Conclusions: This original, host-targeted, drug repurposing strategy constitutes an effective and 64 highly reactive process for the rapid identification of novel anti-infectious drugs, with potential 65 major implications for the management of antimicrobial resistance and the rapid response to 66 future epidemic or pandemic (re)emerging diseases for which we are still disarmed. 67 68 5 Background 69 Besides their well-known pandemic potential, annual outbreaks caused by influenza viruses 70 account for several million respiratory infections and 250,000 to 500,000 deaths worldwide [1]. 71 This global high morbidity and mortality of influenza infections represents a major and recurrent 72 public health threat with high economic burden. In this context, the suboptimal vaccine coverage 73 and efficacy, coupled with recurrent events of viral resistance against a very limited antiviral 74 portfolio, emphasize an urgent need for innovative treatment strategies presenting fewer 75 obstacles for their clinical use [2]. 76 For decades, the strategy for antiviral development was mostly based on serial screenings of 77 hundreds of thousand...

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La modulation de la signature transcriptomique de l’hôte infecté : une nouvelle stratégie thérapeutique dans les viroses graves ? Exemple de la grippe

Cited by 3 publications

References 62 publications

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

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

Séquençage à haut débit pour le diagnostic en maladies infectieuses : exemple de la métagénomique shotgun dans les infections du système nerveux central

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

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