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

AI Article Synopsis

  • Researchers have developed a reliable phenotypic screening method using caspase 3/7 activity to identify potential anti-SARS-CoV-2 compounds, which works across various SARS-CoV-2 variants and other coronaviruses.* -
  • The Caco-2-F03 cell line proved to be the most effective model, as it consistently showed susceptibility to SARS-CoV-2 without yielding misleading results due to drug-related effects.* -
  • A screening of 1,796 kinase inhibitors revealed both known and novel antiviral candidates, with the PHGDH inhibitor NCT-503 showing enhanced activity when combined with clinical candidate 2-deoxy-D-glucose.*

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9822553PMC
http://dx.doi.org/10.1016/j.isci.2023.105944DOI Listing

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