Identification of novel antiviral drug candidates using an optimized SARS-CoV-2 phenotypic screening platform
© 2023 The Authors..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:26 |
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| Enthalten in: |
iScience - 26(2023), 2 vom: 17. Feb., Seite 105944 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Bojkova, Denisa [VerfasserIn] |
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| Anmerkungen: |
Date Revised 02.02.2023 published: Print-Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1016/j.isci.2023.105944 |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM35155212X |
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| 520 | |a © 2023 The Authors. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a Screening in health technology | |
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| 700 | 1 | |a Reus, Philipp |e verfasserin |4 aut | |
| 700 | 1 | |a Panosch, Leona |e verfasserin |4 aut | |
| 700 | 1 | |a Bechtel, Marco |e verfasserin |4 aut | |
| 700 | 1 | |a Rothenburger, Tamara |e verfasserin |4 aut | |
| 700 | 1 | |a Kandler, Joshua D |e verfasserin |4 aut | |
| 700 | 1 | |a Pfeiffer, Annika |e verfasserin |4 aut | |
| 700 | 1 | |a Wagner, Julian U G |e verfasserin |4 aut | |
| 700 | 1 | |a Shumliakivska, Mariana |e verfasserin |4 aut | |
| 700 | 1 | |a Dimmeler, Stefanie |e verfasserin |4 aut | |
| 700 | 1 | |a Olmer, Ruth |e verfasserin |4 aut | |
| 700 | 1 | |a Martin, Ulrich |e verfasserin |4 aut | |
| 700 | 1 | |a Vondran, Florian W R |e verfasserin |4 aut | |
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| 700 | 1 | |a Michaelis, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Cinatl, Jindrich |c Jr |e verfasserin |4 aut | |
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