Repurposing of host-based therapeutic agents for the treatment of coronavirus disease 2019 (COVID-19): a link between antiviral and anticancer mechanisms?

Alonso, Daniel F.; Fariña, Hernán G.

doi:10.1016/j.ijantimicag.2020.106125

Cited by 7 publications

(8 citation statements)

References 24 publications

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“…Drugs such as ivermectin can be used to target viral entry or viral replication mechanisms in host cells, as well as to modulate the innate immune responses, to achieve indirect antiviral activity in vivo. Mechanisms essential for viral infection, such as nuclear transport or intracellular signal transduction, among others, have been indicated as better targets to identify broad-spectrum antiviral agents, with some advantages over direct-acting antivirals targeting viral components [35].…”

Section: Discussionmentioning

confidence: 99%

Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial

et al. 2021

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Section: Discussionmentioning

confidence: 99%

Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial

et al. 2021

Self Cite

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“…Many drugs with potential effects in COVID-19 infection have also been previously explored as repurposed options for cancer treatment, and suggestive similarities were found to exist between antitumor and host-based antiviral mechanisms [3]. Clinically approved drugs could be used to target intracellular mechanisms in host cells that are essential for viral replication.…”

Section: Introductionmentioning

confidence: 99%

“…Beyond the obvious importance of dosing schedules and tissue concentrations of IVM, it is also attractive to search for drug combinations that could potentiate its antiviral mechanism in host cells. Lipophilic statins used in the treatment of hypercholesterolemia such as atorvastatin (ATV) are well-tolerated compounds with antitumor activity that are interesting host-based drug candidates for SARS-CoV-2 in combination with IVM [3]. It is known that statins reduce membrane localization of Rho GTPases, thus affecting intracellular signaling involved in the organization of actin cytoskeleton during the metastatic process [8].…”

Section: Introductionmentioning

confidence: 99%

Effect of Ivermectin and Atorvastatin on Nuclear Localization of Importin Alpha and Drug Target Expression Profiling in Host Cells from Nasopharyngeal Swabs of SARS-CoV-2- Positive Patients

Segatori

Garona

Caligiuri

et al. 2021

Viruses

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Nuclear transport and vesicle trafficking are key cellular functions involved in the pathogenesis of RNA viruses. Among other pleiotropic effects on virus-infected host cells, ivermectin (IVM) inhibits nuclear transport mechanisms mediated by importins and atorvastatin (ATV) affects actin cytoskeleton-dependent trafficking controlled by Rho GTPases signaling. In this work, we first analyzed the response to infection in nasopharyngeal swabs from SARS-CoV-2-positive and -negative patients by assessing the gene expression of the respective host cell drug targets importins and Rho GTPases. COVID-19 patients showed alterations in KPNA3, KPNA5, KPNA7, KPNB1, RHOA, and CDC42 expression compared with non-COVID-19 patients. An in vitro model of infection with Poly(I:C), a synthetic analog of viral double-stranded RNA, triggered NF-κB activation, an effect that was halted by IVM and ATV treatment. Importin and Rho GTPases gene expression was also impaired by these drugs. Furthermore, through confocal microscopy, we analyzed the effects of IVM and ATV on nuclear to cytoplasmic importin α distribution, alone or in combination. Results showed a significant inhibition of importin α nuclear accumulation under IVM and ATV treatments. These findings confirm transcriptional alterations in importins and Rho GTPases upon SARS-CoV-2 infection and point to IVM and ATV as valid drugs to impair nuclear localization of importin α when used at clinically-relevant concentrations.

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“…It is thus quite naturally that this molecule was rapidly considered as a potential repurposing candidate for COVID-19 management (13)(14)(15)(16)(17)(18). NTZ was one of the first molecules studied in vitro against SARS-CoV-2.…”

Section: Introductionmentioning

confidence: 99%

Pre-clinical evaluation of antiviral activity of nitazoxanide against Sars-CoV-2

Driouich

Cochin

Touret

et al. 2021

Preprint

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To address the emergence of SARS-CoV-2, multiple clinical trials in humans were rapidly started, including those involving an oral treatment by nitazoxanide, despite no or limited pre-clinical evidence of antiviral efficacy. In this work, we present a complete pre-clinical evaluation of the antiviral activity of nitazoxanide against SARS-CoV-2. First, we confirmed the in vitro efficacy of nitazoxanide and tizoxanide (its active metabolite) against SARS-CoV-2. Then, we demonstrated nitazoxanide activity in a reconstructed bronchial human airway epithelium model. In a SARS-CoV-2 virus challenge model in hamsters, oral and intranasal treatment with nitazoxanide failed to impair viral replication in commonly affected organs. We hypothesized that this could be due to insufficient diffusion of the drug into organs of interest. Indeed, our pharmacokinetic study confirmed that concentrations of tizoxanide in organs of interest were always below the in vitro EC50. These preclinical results suggest, if directly applicable to humans, that the standard formulation and dosage of nitazoxanide is not effective in providing antiviral therapy for Covid-19.

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Repurposing of host-based therapeutic agents for the treatment of coronavirus disease 2019 (COVID-19): a link between antiviral and anticancer mechanisms?

Cited by 7 publications

References 24 publications

Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial

Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial

Effect of Ivermectin and Atorvastatin on Nuclear Localization of Importin Alpha and Drug Target Expression Profiling in Host Cells from Nasopharyngeal Swabs of SARS-CoV-2- Positive Patients

Pre-clinical evaluation of antiviral activity of nitazoxanide against Sars-CoV-2

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