Differentially conserved amino acid positions may reflect differences in SARS-CoV-2 and SARS-CoV behaviour

Bojkova, Denisa; McGreig, Jake E; McLaughlin, Katie-May; Masterson, Stuart G; Antczak, Magdalena; Widera, Marek; Krähling, Verena; Ciesek, Sandra; Wass, Mark N.; Michaelis, Martin; Cinatl, Jindrich

doi:10.1093/bioinformatics/btab094

Cited by 8 publications

(20 citation statements)

References 48 publications

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“…The human colon carcinoma Caco-2 cell line was established by Jorgen Fogh (Memorial Sloan-Kettering Cancer Center, New York) in 1974 [Fogh et al, 1977] and has been used for the cultivation of human pathogenic viruses including influenza viruses and coronaviruses since 1985 [Reigel, 1985; Collins, 1990; Chan et al, 2013a]. We already used Caco-2 cells (obtained from DSMZ, Braunschweig, Germany) for the cultivation of the close SARS-CoV-2 relative SARS-CoV starting in 2003 [Cinatl et al, 2003; Cinatl et al, 2004] and they also enabled us and others to quickly cultivate SARS-CoV-2 isolates when this novel virus emerged [Bojkova et al, 2020; Bojkova et al, 2020a; Bojkova et al, 2020b; Hoehl et al, 2020; Klann et al, 2020; Toptan et al, 2020; Bojkova et al, 2021; Ellinger et al, 2021; Gower et al, 2021; Widera et al, 2021].…”

Section: Resultsmentioning

confidence: 99%

“…In our hands, Caco-2 cells (obtained from DSMZ, Braunschweig, Germany at the time) have been highly permissive to SARS-CoV and SARS-CoV-2 and developed a pronounced cytopathogenic effect (CPE) in response to infection with both viruses [Cinatl et al, 2003; Cinatl et al, 2004; Bojkova et al, 2020b; Bojkova et al, 2021]. In other studies, however, Caco-2 cells displayed low SARS-CoV-2 susceptibility and no CPE formation [Chu et al, 2020; Lee et al, 2020; Yeung et al, 2021].…”

Section: Resultsmentioning

confidence: 99%

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Identification of novel antiviral drug candidates using an optimized SARS-CoV-2 phenotypic screening platform

Bojkova

Reus

Panosch

et al. 2022

Preprint

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Reliable, easy-to-handle phenotypic screening platforms are needed for the identification of anti-SARS-CoV-2 compounds. Here, we present caspase 3/7 activity as a read-out for monitoring the replication of SARS-CoV-2 isolates from different variants, including a remdesivir-resistant strain, and of other coronaviruses in a broad range of cell culture models, independently of cytopathogenic effect formation. Compared to other cell culture models, the Caco-2 subline Caco-2-F03 displayed superior performance, as it possesses a stable SARS-CoV-2 susceptible phenotype and does not produce false-positive hits due to drug-induced phospholipidosis. A proof-of-concept screen of 1796 kinase inhibitors identified known and novel antiviral drug candidates including inhibitors of PHGDH, CLK-1, and CSF1R. The activity of the PHGDH inhibitor NCT-503 was further increased in combination with the HK2 inhibitor 2-deoxy-D-glucose, which is in clinical development for COVID-19. In conclusion, caspase 3/7 activity detection in SARS-CoV-2-infected Caco-2F03 cells provides a simple phenotypic high-throughput screening platform for SARS-CoV-2 drug candidates that reduces false positive hits.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Identification of novel antiviral drug candidates using an optimized SARS-CoV-2 phenotypic screening platform

Bojkova

Reus

Panosch

et al. 2022

Preprint

Self Cite

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“…We believe that this hypothesis is unlikely, as it would imply that viral particles are able to cross endothelial cells, basement membranes, and interstitial spaces in the lung before finally reaching alveolar epithelial cells. Although the ACE2 receptor is expressed by diverse cells from several organs, the level of expression of ACE2 in a given cell type is not a reliable predictor of the susceptibility of that cell to SARS-CoV-2 infection (Oritz et al 2020 ; Bojkova et al 2021 ). Even in the worst-case scenario of a cornea transplant from an asymptomatic SARS-CoV-2—positive donor, the available evidence and the results presented herein suggest that the risk of a transplant recipient developing a respiratory infection typical of COVID-19 appears to be very low.…”

Section: Discussionmentioning

confidence: 99%

The estimated risk of SARS-CoV- 2 infection via cornea transplant in Canada

O’Brien

Lewin

et al. 2021

Cell Tissue Bank

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In late 2019 the respiratory illness, Corona Virus Disease-19 caused by the SARS-CoV-2 virus emerged in China and quickly spread to other countries. The primary mode of transmission is person-to-person via respiratory droplets. SARS-CoV-2 has been identified in conjunctiva. Transmission by cornea transplant has not been reported but is theoretically possible. We aimed to estimate the possible risk of transmission in Canada via cornea transplant during the first wave of the pandemic, and the potential risk reduction from testing decedents. We constructed a deterministic model in which the risk of transmission was estimated as the product of three proportions: decedents with SARS-CoV-2 infection, corneas that are NAT positive, and NAT positive corneas presumed to transmit. Risk was estimated according to 3 scenarios: most likely, optimistic and pessimistic. At the peak of the first wave of the pandemic risk was estimated to be 1 in 63,031 cornea transplants in Canada but could be as low as 1 in 175,821 or as high as 1 in 10,129. It would take 16 years at the peak infection of the first wave of the pandemic to observe 1 transmission. Testing would reduce the risk of 1 in 63,031 to 1 in 210,104 assuming 70% test sensitivity. The theoretical risk of SARS-CoV-2 transmission by cornea transplant is extremely low and decedent testing is unlikely to be beneficial.

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“…4A ) ( 288 , 289 ). In Calu-3 and Caco-2 cells, camostat inhibits SARS-CoV and SARS-CoV-2 with EC 50 s generally below 1 μM, while the EC 50 s for nafamostat are generally ∼10-fold lower ( 130 , 287 , 290 , 291 ). These compounds, however, are largely inactive in Vero cells because Vero cells do not require TMPRSS2 for virus entry ( 63 , 131 , 287 ).…”

Section: Host-targeting Compoundsmentioning

confidence: 99%

SARS-CoV-2 Antiviral Therapy

et al. 2021

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The development of effective antiviral therapy for COVID-19 is critical for those awaiting vaccination, as well as for those who do not respond robustly to vaccination. This review summarizes 1 year of progress in the race to develop antiviral therapies for COVID-19, including research spanning preclinical and clinical drug development efforts, with an emphasis on antiviral compounds that are in clinical development or that are high priorities for clinical development.

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Differentially conserved amino acid positions may reflect differences in SARS-CoV-2 and SARS-CoV behaviour

Cited by 8 publications

References 48 publications

Identification of novel antiviral drug candidates using an optimized SARS-CoV-2 phenotypic screening platform

Identification of novel antiviral drug candidates using an optimized SARS-CoV-2 phenotypic screening platform

The estimated risk of SARS-CoV- 2 infection via cornea transplant in Canada

SARS-CoV-2 Antiviral Therapy

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