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

  • 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.

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Author:Denisa BojkovaORCiDGND, Philipp ReusORCiD, Leona Panosch, Marco Bechtel, Tamara RothenburgerORCiD, Joshua D. KandlerORCiD, Annika Eby PfeifferORCiDGND, Julian Uwe Gabriel WagnerORCiDGND, Mariana ShumliakivskaORCiD, Stefanie DimmelerORCiDGND, Ruth Maria OlmerGND, Ulrich MartinORCiDGND, Florian VondranORCiDGND, Tuna ToptanORCiDGND, Florian RothweilerGND, Richard ZehnerORCiDGND, Holger RabenauORCiDGND, Karen L. OsmanORCiD, Steven T. PullanORCiD, Miles CarrollORCiD, Richard StackORCiD, Sandra CiesekORCiDGND, Mark N. WassORCiD, Martin MichaelisORCiDGND, Jindrich CinatlORCiDGND
URN:urn:nbn:de:hebis:30:3-733509
DOI:https://doi.org/10.1016/j.isci.2023.105944
ISSN:2589-0042
Parent Title (English):iScience
Publisher:Elsevier
Place of publication:Amsterdam u.a.
Document Type:Article
Language:English
Year of Completion:2023
Year of first Publication:2023
Publishing Institution:Universit├Ątsbibliothek Johann Christian Senckenberg
Release Date:2023/07/15
Volume:26
Issue:105944
Page Number:24
First Page:1
Last Page:23
HeBIS-PPN:512572615
Institutes:Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universit├Ątspublikationen
Licence (German):License LogoCreative Commons - Namensnennung-Nicht kommerziell - Keine Bearbeitung 4.0