TY  - INPR
A1  - Bojkova, Denisa
A1  - Reus, Philipp
A1  - Panosch, Leona
A1  - Bechtel, Marco
A1  - Rothenburger, Tamara
A1  - Kandler, Joshua D.
A1  - Pfeiffer, Annika Eby
A1  - Wagner, Julian Uwe Gabriel
A1  - Shumliakivska, Mariana
A1  - Dimmeler, Stefanie
A1  - Olmer, Ruth Maria
A1  - Martin, Ulrich
A1  - Vondran, Florian
A1  - Toptan, Tuna
A1  - Rothweiler, Florian
A1  - Zehner, Richard
A1  - Rabenau, Holger
A1  - Osman, Karen L.
A1  - Pullan, Steven T.
A1  - Carroll, Miles
A1  - Stack, Richard
A1  - Ciesek, Sandra
A1  - Wass, Mark N.
A1  - Michaelis, Martin
A1  - Cinatl, Jindrich
T1  - Identification of novel antiviral drug candidates using an optimized SARS-CoV-2 phenotypic screening platform
T2  - bioRxiv
N2  - 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.
Y1  - 2022
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/73079
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-730792
IS  - 2022.07.17.500346
ER  -