Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection

Fantini, Jacques; Scala, Coralie Di; Chahinian, Henri; Yahi, Nouara

doi:10.1016/j.ijantimicag.2020.105960

Cited by 527 publications

(648 citation statements)

References 29 publications

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“…In contrast to these findings, a randomized double blind placebo controlled trial of 400 mg of HCQ failed to find any difference in T cell activation and reported increased viral replication [33]. While in vitro data of SARS-CoV-2 provide compelling rationale for suggesting clinical efficacy of HCQ [4,34], in vivo data and randomized double blinded placebo COVID-19 studies of HCQ are needed to account of contextdependent effects of the host being administered HCQ. Further work will need to determine whether the mechanism of action of HCQ is directly impacting SARS-CoV-2 or indirectly impacting the immune system and hence indiscriminately improving COVID-19 clinical outcomes.…”

Section: Hcq-related Transcriptional Changes In Macrophages Minimallymentioning

confidence: 96%

Comparativein vitrotranscriptomic analyses of COVID-19 candidate therapy hydroxychloroquine suggest limited immunomodulatory evidence of SARS-CoV-2 host response genes

Corley

Sugai

Schotsaert

et al. 2020

Preprint

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Hydroxychloroquine (HCQ) has emerged as a potential and controversial antiviral candidate therapy for COVID-19. While many clinical trials are underway to test the efficacy of HCQ as a treatment for COVID-19, underlying mechanisms of HCQ in the setting of COVID-19 remain unclear. Hence, we examined differential gene expression signatures of HCQ exposure, in vitro SARS-CoV-2 infection, and host signatures of COVID-19 in blood, bronchoalveolar lavage, and postmortem lung to evaluate whether HCQ transcriptome signatures associate with restoration of SARS-CoV-2-related host transcriptional responses. Here, we show that 24 hours of in vitro treatment of peripheral blood mononuclear cells(PBMC) with HCQ significantly impacted transcription of 16 genes involved in immune regulation and lipid metabolism. Using transcriptome data from in vitro SARS-CoV-2 infected NHBE and A549 cells and PBMC derived from confirmed COVID-19 infected patients, we determined that only 0.24% of the COVID-19 PBMC differentially expressed gene set and 0.39% of the in vitro SARS-CoV-2 cells differentially expressed gene set overlapped with HCQ-related differentially expressed genes. Moreover, we observed that HCQ treatment significantly impacted transcription of 159 genes in human primary monocyte-derived macrophages involved in cholesterol biosynthetic process and chemokine activity. Notably, when we compared the macrophage HCQ-related gene lists with genes transcriptionally altered during SARS-CoV-2 infection and in bronchoalveolar lavage of COVID-19+ patients, the CXCL6 gene was impacted in all three transcriptional signatures revealing evidence in favor of chemokine modulation. HCQrelated transcriptional changes minimally overlapped with host genes altered in postmortem lung biopsies from COVID-19 participants. These results may provide insight into the immunomodulation mechanisms of HCQ treatment in the setting of COVID-19 and suggest HCQ is not a panacea to SARS-CoV-2 infection.was not certified by peer review)

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Section: Hcq-related Transcriptional Changes In Macrophages Minimallymentioning

confidence: 96%

Comparativein vitrotranscriptomic analyses of COVID-19 candidate therapy hydroxychloroquine suggest limited immunomodulatory evidence of SARS-CoV-2 host response genes

Corley

Sugai

Schotsaert

et al. 2020

Preprint

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“…It was recently suggested that chloroquine (CQ) and hydroxychloroquine (HCQ) may be useful in the treatment of COVID-19, but presently there is inadequate evidence to support their safe and effective treatment of COVID-19 [33]. There is emerging evidence suggesting that CQ and HCQ may directly impact cornavirus attachment to respiratory cells [34], but there is also interesting potential modes of action for these drugs with respect to respiratory conditions associated with COVID-19. Namely, it was revealed that CQ and HCQ have the ability to significantly increase cellular hemoglobin production [35] and it was suggested that such drugs may have a therapeutic potential to raise hemoglobin levels in patients [36].…”

Section: Chloroquine/hydroxychloroquine Treatmentsmentioning

confidence: 99%

Respiratory conditions in coronavirus disease 2019 (COVID-19): Important considerations regarding novel treatment strategies to reduce mortality

Geier¹,

Geier²

2020

Medical Hypotheses

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“…These data suggest that SARS-CoV-2 entry partially relies on clathrin-mediated endocytosis and cellular cathepsins that cleave the viral Spike protein allowing for viral fusion once SARS-CoV-2 is internalized in endosomes. However, as hydroxychloroquine activity was much more potent than that exerted by Amantadine or E64-d, it will be paramount to dissect other possible pathways that could be responsible for the potent antiviral effect of hydroxychloroquine (Fantini et al, 2020).…”

Section: Antiviral Activity Of Compounds That Potentially Inhibit Virmentioning

confidence: 99%

Identification of Plitidepsin as Potent Inhibitor of SARS-CoV-2-Induced Cytopathic Effect after a Drug Repurposing Screen

Rodón

Muñoz-Basagoiti

Perez-Zsolt

et al. 2020

Preprint

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196)Different treatments are currently used for clinical management of SARS-CoV-2 infection, but little is known about their efficacy yet. Here we present ongoing results to compare currently available drugs for a variety of diseases to find out if they counteract SARS-CoV-2-induced cytopathic effect in vitro. Our goal is to prioritize antiviral activity to provide a solid evidence-driven rationale for forthcoming clinical trials.Since the most effective antiviral approaches are usually based on combined therapies that tackle the viral life cycle at different stages, we are also testing combinations of drugs that may be critical to reduce the emergence of resistant viruses. We will provide results as soon as they become available, so data should be interpreted with caution, clearly understanding the limitations of the in vitro model, that may not always reflect what could happen in vivo. Thus, our goal is to test the most active antivirals identified in adequate animal models infected with SARS-CoV-2, to add more information about possible in vivo efficacy. In turn, successful antivirals could be tested in clinical trials as treatments for infected patients, but also as pre-exposure prophylaxis to avoid novel infections until an effective and safe vaccine is developed.

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Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection

Cited by 527 publications

References 29 publications

Comparativein vitrotranscriptomic analyses of COVID-19 candidate therapy hydroxychloroquine suggest limited immunomodulatory evidence of SARS-CoV-2 host response genes

Comparativein vitrotranscriptomic analyses of COVID-19 candidate therapy hydroxychloroquine suggest limited immunomodulatory evidence of SARS-CoV-2 host response genes

Respiratory conditions in coronavirus disease 2019 (COVID-19): Important considerations regarding novel treatment strategies to reduce mortality

Identification of Plitidepsin as Potent Inhibitor of SARS-CoV-2-Induced Cytopathic Effect after a Drug Repurposing Screen

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