Bojkova, Denisa, Reus, Philipp, Panosch, Leona, Bechtel, Marco, Rothenburger, Tamara, Kandler, Joshua D, Pfeiffer, Annika, Wagner, Julian U G, Shumliakivska, Mariana, Dimmeler, Stefanie, and others. (2023) Identification of novel antiviral drug candidates using an optimized SARS-CoV-2 phenotypic screening platform. iScience, 26 (2). Article Number 105944. ISSN 2589-0042. (doi:10.1016/j.isci.2023.105944) (KAR id:99758)
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Language: English 
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| Official URL: https://doi.org/10.1016/j.isci.2023.105944 |
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Abstract
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 readout for monitoring the replication of SARS-CoV-2 isolates from different variants, including a remdesivir-resistant strain, and of other coronaviruses in numerous cell culture models, independently of cytopathogenic effect formation. Compared to other models, the Caco-2 subline Caco-2-F03 displayed superior performance. It possesses a stable SARS-CoV-2 susceptibility phenotype and does not produce false-positive hits due to drug-induced phospholipidosis. A proof-of-concept screen of 1,796 kinase inhibitors identified known and novel antiviral drug candidates including inhibitors of phosphoglycerate dehydrogenase (PHGDH), CDC like kinase 1 (CLK-1), and colony stimulating factor 1 receptor (CSF1R). The activity of the PHGDH inhibitor NCT-503 was further increased in combination with the hexokinase II (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-2-F03 cells provides a simple phenotypic high-throughput screening platform for SARS-CoV-2 drug candidates that reduces false-positive hits. [Abstract copyright: © 2023 The Authors.]
| Item Type: | Article |
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| DOI/Identification number: | 10.1016/j.isci.2023.105944 |
| Additional information: | For the purpose of open access, the author(s) has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising. |
| Uncontrolled keywords: | Drugs, Screening in health technology, Virology |
| Subjects: | Q Science > QH Natural history > QH301 Biology |
| Divisions: | Divisions > Division of Natural Sciences > Biosciences |
| Funders: | Biotechnology and Biological Sciences Research Council (https://ror.org/00cwqg982) |
| SWORD Depositor: | JISC Publications Router |
| Depositing User: | JISC Publications Router |
| Date Deposited: | 01 Feb 2023 14:47 UTC |
| Last Modified: | 20 Nov 2023 15:39 UTC |
| Resource URI: | https://kar.kent.ac.uk/id/eprint/99758 (The current URI for this page, for reference purposes) |
University of Kent Author Information
Stack, Richard.
| Creator's ORCID: | |
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| CReDIT Contributor Roles: |
Wass, Mark N..
| Creator's ORCID: |
 https://orcid.org/0000-0001-5428-6479
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|---|---|
| CReDIT Contributor Roles: |
Michaelis, Martin.
| Creator's ORCID: |
https://orcid.org/0000-0002-5710-5888
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| CReDIT Contributor Roles: |
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