Interferon system deficiencies exacerbating severe pandemic virus infections

Stertz, Silke; Hale, Benjamin G.

doi:10.1016/j.tim.2021.03.001

“…Furthermore, it was shown that some patients with life-threatening COVID-19 had neutralizing IgG auto-antibodies against IFN-ω, IFN-α, or both. These antibodies prevent the corresponding type I IFNs from blocking SARS-CoV-2 infection in vitro and were not found in patients with mild COVID-19 or asymptomatic individuals [487,488]. Altogether, these data strongly support the notion that dysregulated type I IFN immunity underlies life-threatening COVID-19 pneumonia.…”

Section: Interferon Responsesupporting

confidence: 51%

SARS-CoV-2 Portrayed Against HIV: Contrary Viral Strategies in Similar Disguise

Duerr¹,

Jimenez²,

Dittmann³

2021

Preprint

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SARS-CoV-2 and HIV are zoonotic viruses that rapidly reached pandemic scale causing global losses and fear. The COVID-19 and AIDS pandemics ignited massive efforts worldwide to develop antiviral strategies and characterize viral architectures, biological and immunological properties, and clinical outcomes. Although both viruses have a comparable appearance as enveloped, positive-stranded RNA viruses with envelope spikes mediating cellular entry, the entry process, downstream biological and immunological pathways, clinical outcomes, and disease courses are strikingly different. This review provides a systemic comparison of both viruses’ structural and functional characteristics delineating their distinct strategies for efficient spread.

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“…Infection with SARS-CoV-2 results in a respiratory disease, COVID-19, that is mild in many individuals or even asymptomatic. However, in vulnerable patients, in particular individuals with compromised immune systems, such as the elderly, immunosuppressed or those with other chronic diseases, the virus can cause a severe life-threatening pneumonia [2][3][4][5]. Thus, large efforts have been undertaken to develop vaccines and antiviral drugs for the prevention and treatment of COVID-19.…”

Section: Introductionmentioning

confidence: 99%

Combined computational and cellular screening identifies synergistic inhibition of SARS-CoV-2 by lenvatinib and remdesivir

Pohl

¹

,

Busnadiego

²

,

Marrafino

³

et al. 2021

Journal of General Virology

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Rapid repurposing of existing drugs as new therapeutics for COVID-19 has been an important strategy in the management of disease severity during the ongoing SARS-CoV-2 pandemic. Here, we used high-throughput docking to screen 6000 compounds within the DrugBank library for their potential to bind and inhibit the SARS-CoV-2 3 CL main protease, a chymotrypsin-like enzyme that is essential for viral replication. For 19 candidate hits, parallel in vitro fluorescence-based protease-inhibition assays and Vero-CCL81 cell-based SARS-CoV-2 replication-inhibition assays were performed. One hit, diclazuril (an investigational anti-protozoal compound), was validated as a SARS-CoV-2 3 CL main protease inhibitor in vitro (IC50 value of 29 µM) and modestly inhibited SARS-CoV-2 replication in Vero-CCL81 cells. Another hit, lenvatinib (approved for use in humans as an anti-cancer treatment), could not be validated as a SARS-CoV-2 3 CL main protease inhibitor in vitro, but serendipitously exhibited a striking functional synergy with the approved nucleoside analogue remdesivir to inhibit SARS-CoV-2 replication, albeit this was specific to Vero-CCL81 cells. Lenvatinib is a broadly-acting host receptor tyrosine kinase (RTK) inhibitor, but the synergistic effect with remdesivir was not observed with other approved RTK inhibitors (such as pazopanib or sunitinib), suggesting that the mechanism-of-action is independent of host RTKs. Furthermore, time-of-addition studies revealed that lenvatinib/remdesivir synergy probably targets SARS-CoV-2 replication subsequent to host-cell entry. Our work shows that combining computational and cellular screening is a means to identify existing drugs with repurposing potential as antiviral compounds. Future studies could be aimed at understanding and optimizing the lenvatinib/remdesivir synergistic mechanism as a therapeutic option.

show abstract

“…Infection with SARS-CoV-2 results in a respiratory disease, COVID-19, that is mild in many individuals or even asymptomatic. However, in vulnerable patients, in particular individuals with compromised immune systems, such as the elderly, immunosuppressed or those with other chronic diseases, the virus can cause a severe life-threatening pneumonia [2-5]. Thus, large efforts have been undertaken to develop vaccines and antiviral drugs for the prevention and treatment of COVID-19.…”

Section: Introductionmentioning

confidence: 99%

Combined computational and cellular screening identifies synergistic inhibition of SARS-CoV-2 by lenvatinib and remdesivir

Pohl

¹

,

Busnadiego

²

,

Marrafino

³

et al. 2021

Preprint

Self Cite

0

View full text Add to dashboard Cite

Rapid repurposing of existing drugs as new therapeutics for COVID-19 has been an important strategy in the management of disease severity during the ongoing SARS-CoV-2 pandemic. Here, we screened by high-throughput docking 6,000 compounds within the DrugBank library for their potential to bind and inhibit the SARS-CoV-2 3CL main protease, a chymotrypsin-like enzyme that is essential for viral replication. For 19 candidate hits, parallel in vitro fluorescence-based protease-inhibition assays and Vero-CCL81 cell-based SARS-CoV-2 replication-inhibition assays were performed. One hit, diclazuril (an investigational anti-protozoal compound), was validated as a SARS-CoV-2 3CL main protease inhibitor in vitro (IC50 value of 29 μM) and modestly inhibited SARS-CoV-2 replication in Vero-CCL81 cells. Another hit, lenvatinib (approved for use in humans as an anti-cancer treatment), could not be validated as a SARS-CoV-2 3CL main protease inhibitor in vitro, but serendipitously exhibited a striking functional synergy with the approved nucleoside analogue remdesivir to inhibit SARS-CoV-2 replication in Vero-CCL81 cells. Lenvatinib is a broadly-acting host receptor tyrosine kinase (RTK) inhibitor, but the synergistic effect with remdesivir was not observed with other approved RTK inhibitors (such as pazopanib or sunitinib), suggesting that the mechanism-of-action is independent of host RTKs. Furthermore, time-of-addition studies revealed that lenvatinib/remdesivir synergy probably targets SARS-CoV-2 replication subsequent to host-cell entry. Our study shows that combining computational and cellular screening is an efficient means to identify existing drugs with repurposing potential as antiviral compounds. Future studies should aim at understanding and optimizing the lenvatinib/remdesivir synergistic mechanism as a therapeutic option.IMPORTANCESuccessful repurposing of existing drugs as COVID-19 therapeutics would be a rapid and important means to limit disease severity during the SARS-CoV-2 pandemic. In this study, we used a computational screening approach to identify existing drugs that might inhibit the function of a critical enzyme (the 3CL main protease) encoded by the causative agent of COVID-19, SARS-CoV-2. While we found that diclazuril (an investigational human drug already approved for use in animals) inhibited this viral enzyme in vitro, it only showed modest ability to inhibit SARS-CoV-2 replication in cells. However, our approach serendipitously identified lenvatinib (an anti-cancer drug approved for use in humans) as a potent inhibitor of SARS-CoV-2 replication when combined with the existing approved antiviral drug, remdesivir. Our findings raise the possibility that future studies to understand the molecular mechanisms underlying the lenvatinib/remdesivir synergy could uncover new therapeutic principles for treatment of COVID-19 or similar viral diseases.

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Interferon system deficiencies exacerbating severe pandemic virus infections

Cited by 51 publications

References 64 publications

SARS-CoV-2 Portrayed Against HIV: Contrary Viral Strategies in Similar Disguise

SARS-CoV-2 Portrayed Against HIV: Contrary Viral Strategies in Similar Disguise

Combined computational and cellular screening identifies synergistic inhibition of SARS-CoV-2 by lenvatinib and remdesivir

Combined computational and cellular screening identifies synergistic inhibition of SARS-CoV-2 by lenvatinib and remdesivir

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