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10.3390/v13020173 http://scihub22266oqcxt.onion/10.3390/v13020173 33498923!7911889!33498923     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=33498923&cmd=llinks): Failed to open stream: HTTP request failed! 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Development of a Cell-Based Luciferase Complementation Assay for Identification of SARS-CoV-2 3CL(pro) Inhibitors |pdf=|usr=}}{{33498923}} gab.com Text Development of a Cell-Based Luciferase Complementation Assay for Identification of SARS-CoV-2 3CL(pro) Inhibitors JO: Viruses http://www.kidney.de/pget.php?&tw=1&pmid=33498923 #FOAvip The 3C-like protease (3CL(pro)) of SARS-CoV-2 is considered an excellent target for COVID-19 antiviral drug development because it is essential for viral replication and has a cleavage specificity distinct from human proteases. However, drug development for 3CL(pro) has been hindered by a lack of cell-based reporter assays that can be performed in a BSL-2 setting. Current efforts to identify 3CL(pro) inhibitors largely rely upon in vitro screening, which fails to account for cell permeability and cytotoxicity of compounds, or assays involving replication-competent virus, which must be performed in a BSL-3 facility. To address these limitations, we have developed a novel cell-based luciferase complementation reporter assay to identify inhibitors of SARS-CoV-2 3CL(pro) in a BSL-2 setting. The assay is based on a lentiviral vector that co-expresses 3CL(pro) and two luciferase fragments linked together by a 3CL(pro) cleavage site. 3CL(pro)-mediated cleavage results in a loss of complementation and low luciferase activity, whereas inhibition of 3CL(pro) results in 10-fold higher levels of luciferase activity. The luciferase reporter assay can easily distinguish true 3CL(pro) inhibition from cytotoxicity, a powerful feature that should reduce false positives during screening. Using the assay, we screened 32 small molecules for activity against SARS-CoV-2 3CL(pro), including HIV protease inhibitors, HCV protease inhibitors, and various other compounds that have been reported to inhibit SARS-CoV-2 3CL(pro). Of these, only five exhibited significant inhibition of 3CL(pro) in cells: GC376, boceprevir, Z-FA-FMK, calpain inhibitor XII, and GRL-0496. This assay should greatly facilitate efforts to identify more potent inhibitors of SARS-CoV-2 3CL(pro). Twit Text FOAVip Development of a Cell-Based Luciferase Complementation Assay for Identification of SARS-CoV-2 3CL(pro) Inhibitors ????Viruses http://www.kidney.de/pget.php?&tw=1&pmid=33498923 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=33498923 #FOAvip English Wikipedia <ref>{{Cite pmid|33498923}}</ref> Development of a Cell-Based Luciferase Complementation Assay for Identification of SARS-CoV-2 3CL(pro) Inhibitors #MMPMID33498923 Rawson JMO; Duchon A; Nikolaitchik OA; Pathak VK; Hu WS Viruses 2021[Jan]; 13 (2): ä PMID33498923show ga The 3C-like protease (3CL(pro)) of SARS-CoV-2 is considered an excellent target for COVID-19 antiviral drug development because it is essential for viral replication and has a cleavage specificity distinct from human proteases. However, drug development for 3CL(pro) has been hindered by a lack of cell-based reporter assays that can be performed in a BSL-2 setting. Current efforts to identify 3CL(pro) inhibitors largely rely upon in vitro screening, which fails to account for cell permeability and cytotoxicity of compounds, or assays involving replication-competent virus, which must be performed in a BSL-3 facility. To address these limitations, we have developed a novel cell-based luciferase complementation reporter assay to identify inhibitors of SARS-CoV-2 3CL(pro) in a BSL-2 setting. The assay is based on a lentiviral vector that co-expresses 3CL(pro) and two luciferase fragments linked together by a 3CL(pro) cleavage site. 3CL(pro)-mediated cleavage results in a loss of complementation and low luciferase activity, whereas inhibition of 3CL(pro) results in 10-fold higher levels of luciferase activity. The luciferase reporter assay can easily distinguish true 3CL(pro) inhibition from cytotoxicity, a powerful feature that should reduce false positives during screening. Using the assay, we screened 32 small molecules for activity against SARS-CoV-2 3CL(pro), including HIV protease inhibitors, HCV protease inhibitors, and various other compounds that have been reported to inhibit SARS-CoV-2 3CL(pro). Of these, only five exhibited significant inhibition of 3CL(pro) in cells: GC376, boceprevir, Z-FA-FMK, calpain inhibitor XII, and GRL-0496. This assay should greatly facilitate efforts to identify more potent inhibitors of SARS-CoV-2 3CL(pro). |Antiviral Agents/*metabolism/pharmacology[MESH] |Cell Survival/drug effects[MESH] |Coronavirus 3C Proteases/*antagonists & inhibitors/genetics/metabolism[MESH] |Drug Evaluation, Preclinical[MESH] |HEK293 Cells[MESH] |Humans[MESH] |Lentivirus/genetics[MESH] |Luciferases/genetics/*metabolism[MESH] |Protease Inhibitors/*metabolism/pharmacology[MESH]Development of a Cell-Based Luciferase Complementation Assay for Ident(epmc).pdf DeepDyve Pubget Overpricing