Drug repurposing screens reveal cell-type-specific entry pathways and FDA-approved drugs active against SARS-Cov-2

Dittmar, Mark; Lee, Jae Seung; Whig, Kanupriya; Segrist, Elisha; Li, Minghua; Kamalia, Brinda; Castellana, Lauren; Ayyanathan, Kasirajan; Cardenas-Diaz, Fabian L.; Morrisey, Edward E.; Truitt, Rachel; Yang, Wenli; Jurado, Kellie Ann; Samby, Kirandeep; Ramage, Holly; Schultz, D.; Cherry, Sara

doi:10.1016/j.celrep.2021.108959

Cited by 179 publications

(196 citation statements)

References 119 publications

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“…These cells are the standard cell line used for SARS-CoV and SARS-CoV-2 antiviral screening, as they are highly permissive to virus infections and lack interferon production allowing for CPE observation. However, resent studies [56][57][58][59] suggest that both infection and therapeutic responses might be cell linedependent. Indeed, in an exhaustive study 59 it was reported that only few human cell lines (CaCo-2, Huh7, 293T, and Calu-3), derived from colorectal adenocarcinoma, hepatocellular carcinoma, embryonic kidney, and lung adenocarcinoma respectively, were susceptible to SARS-CoV-2 infection, together with a number of other animal cell lines.…”

Section: Discussionmentioning

confidence: 99%

p‐cymene impairs SARS‐CoV‐2 and Influenza A (H1N1) viral replication: In silico predicted interaction with SARS‐CoV‐2 nucleocapsid protein and H1N1 nucleoprotein

Panagiotopoulos

Tseliou

Karakasiliotis

et al. 2021

Pharmacology Res & Perspec

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Therapeutic regimens for the COVID‐19 pandemics remain unmet. In this line, repurposing of existing drugs against known or predicted SARS‐CoV‐2 protein actions have been advanced, while natural products have also been tested. Here, we propose that p‐cymene, a natural monoterpene, can act as a potential novel agent for the treatment of SARS‐CoV‐2‐induced COVID‐19 and other RNA‐virus‐induced diseases (influenza, rabies, Ebola). We show by extensive molecular simulations that SARS‐CoV‐2 C‐terminal structured domain contains a nuclear localization signal (NLS), like SARS‐CoV, on which p‐cymene binds with low micromolar affinity, impairing nuclear translocation of this protein and inhibiting viral replication, as verified by preliminary in vitro experiments. A similar mechanism may occur in other RNA‐viruses (influenza, rabies and Ebola), also verified in vitro for influenza, by interaction of p‐cymene with viral nucleoproteins, and structural modification of their NLS site, weakening its interaction with importin A. This common mechanism of action renders therefore p‐cymene as a possible antiviral, alone, or in combination with other agents, in a broad spectrum of RNA viruses, from SARS‐CoV‐2 to influenza A infections.

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Section: Discussionmentioning

confidence: 99%

p‐cymene impairs SARS‐CoV‐2 and Influenza A (H1N1) viral replication: In silico predicted interaction with SARS‐CoV‐2 nucleocapsid protein and H1N1 nucleoprotein

Panagiotopoulos

Tseliou

Karakasiliotis

et al. 2021

Pharmacology Res & Perspec

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“…1A) and apilimod (Fig. 1B) (19,25,26). While this mutation has no effect on the virus entry mechanism or sensitivity to proteases, it stabilizes the stalk region of the spike, which otherwise tend to fall apart after furin cleavage between S1 and S2 (27)(28)(29)(30).…”

Section: Combined Use Of Apilimod and Camostat Mesylate Led To Enhanced Inhibition Of Vsv-mentioning

confidence: 99%

Synergistic block of SARS-CoV-2 infection by combined drug inhibition of the host entry factors PIKfyve kinase and TMPRSS2 protease

Kreutzberger

Sanyal

Ojha

et al. 2021

Preprint

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Repurposing FDA-approved inhibitors able to prevent infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could provide a rapid path to establish new therapeutic options to mitigate the effects of coronavirus disease 2019 (COVID-19). Proteolytic cleavages of the spike S protein of SARS-CoV-2, mediated by the host cell proteases cathepsin and TMPRSS2, alone or in combination, are key early activation steps required for efficient infection. The PIKfyve kinase inhibitor apilimod interferes with late endosomal viral traffic, and through an ill-defined mechanism prevents in vitro infection through late endosomes mediated by cathepsin. Similarly, inhibition of TMPRSS2 protease activity by camostat mesylate or nafamostat mesylate prevents infection mediated by the TMPRSS2-dependent and cathepsin-independent pathway. Here, we combined the use of apilimod with camostat mesylate or nafamostat mesylate and found an unexpected ~5-10 fold increase in their effectiveness to prevent SARS-CoV-2 infection in different cell types. Comparable synergism was observed using both, a chimeric vesicular stomatitis virus (VSV) containing S of SARS-CoV-2 (VSV-SARS-CoV-2) and SARS-CoV-2 virus. The substantial ~5 fold or more decrease of half maximal effective concentrations (EC50 values) suggests a plausible treatment strategy based on the combined use of these inhibitors.

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“…It was shown that hydroxychloroquine potently inhibited SARS-CoV-2 in an African green monkey kidney cell model. However, a recent study showed that hydroxychloroquine barely exerts antiviral activity in Calu-3 cells, a lung-derived epithelial cell line [ 46 ]. Furthermore, hydroxychloroquine failed to exert an anti-SARS-CoV-2 effect in a model of reconstituted human airway epithelium and in human clinical trials [ 56 , 57 ].…”

Section: Drug Repurposing For Covid-19mentioning

confidence: 99%

“…The study showed that baricitinib reduced the mortality by 71% in a large elderly cohort [ 50 ]. Most recently, a screen of ~3000 FDA-approved drugs revealed that cyclosporine showed a micromolar IC50 against SARS-CoV-2 in both Huh7.5 (IC50: 0.87 μM) and Calu-3 cells (IC50: 3.7 μM) [ 46 ].…”

Section: Drug Repurposing For Covid-19mentioning

confidence: 99%

“…Ebastine and mequitazine inhibited SARS-CoV-2 in Vero cells with IC50 values of 6.92 and 7.28 µM, respectively [ 74 ]. Of note, the antiviral activity of ebastine was cell-type-dependent, with an anti-SARS-CoV-2 effect ten-fold less in Vero cells than in Huh7.5 cells [ 46 ]. Loratadine is a H1 receptor antagonist prescribed for the treatment of hay fever and other allergic diseases.…”

Section: Inhibition Of Sars-cov-2 By H1 Receptor Antagonistsmentioning

confidence: 99%

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Could Histamine H1 Receptor Antagonists Be Used for Treating COVID-19?

Fuhler

Pan

2021

IJMS

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COVID-19 has rapidly become a pandemic worldwide, causing extensive and long-term health issues. There is an urgent need to identify therapies that limit SARS-CoV-2 infection and improve the outcome of COVID-19 patients. Unbalanced lung inflammation is a common feature in severe COVID-19 patients; therefore, reducing lung inflammation can undoubtedly benefit the clinical manifestations. Histamine H1 receptor (H1 receptor) antagonists are widely prescribed medications to treat allergic diseases, while recently it has emerged that they show significant promise as anti-SARS-CoV-2 agents. Here, we briefly summarize the novel use of H1 receptor antagonists in combating SARS-CoV-2 infection. We also describe the potential antiviral mechanisms of H1 receptor antagonists on SARS-CoV-2. Finally, the opportunities and challenges of the use of H1 receptor antagonists in managing COVID-19 are discussed.

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Drug repurposing screens reveal cell-type-specific entry pathways and FDA-approved drugs active against SARS-Cov-2

Cited by 179 publications

References 119 publications

p‐cymene impairs SARS‐CoV‐2 and Influenza A (H1N1) viral replication: In silico predicted interaction with SARS‐CoV‐2 nucleocapsid protein and H1N1 nucleoprotein

p‐cymene impairs SARS‐CoV‐2 and Influenza A (H1N1) viral replication: In silico predicted interaction with SARS‐CoV‐2 nucleocapsid protein and H1N1 nucleoprotein

Synergistic block of SARS-CoV-2 infection by combined drug inhibition of the host entry factors PIKfyve kinase and TMPRSS2 protease

Could Histamine H1 Receptor Antagonists Be Used for Treating COVID-19?

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