Abstract
To discover effective drugs for COVID-19 treatment amongst already clinically approved drugs, we developed a high throughput screening assay for SARS-CoV-2 virus entry inhibitors using SARS2-S pseudotyped virus. An approved drug library of 1800 small molecular drugs was screened for SARS2 entry inhibitors and 15 active drugs were identified as specific SARS2-S pseudovirus entry inhibitors. Antiviral tests using native SARS-CoV-2 virus in Vero E6 cells confirmed that 7 of these drugs (clemastine, amiodarone, trimeprazine, bosutinib, toremifene, flupenthixol, and azelastine) significantly inhibited SARS2 replication, reducing supernatant viral RNA load with a promising level of activity. Three of the drugs were classified as histamine receptor antagonists with clemastine showing the strongest anti-SARS2 activity (EC50 = 0.95 ± 0.83 µM). Our work suggests that these 7 drugs could enter into further in vivo studies and clinical investigations for COVID-19 treatment.
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Acknowledgements
This work was supported by the National Key Research and Development Program of China (2018YFC1200604). Experiments related to SARS-CoV-2 were carried out at the National Biosafety Laboratory, Wuhan, Chinese Academy of Sciences. We are particularly grateful to Tao Du and Lun Wang from the Zhengdian Biosafety Level 3 Laboratory and the team running the laboratory for their work. The pNL4.3.Luc.R-.E- plasmid was kindly gifted by Dr Shi-bo Jiang and Dr Lu Lu from Fudan University.
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RJP, YCZ, JX, and SQX worked as a team to perform validation assay involving live SARS2 virus in biosafety level 3 laboratory in Wuhan Institute of Virology; LY performed HTS screening assay; HL conducted pseudovirus package and validation assay; XNM helped in data collection and analysis in HTS assay; YZ, FHZ, PLH, and WT participated in the experiments; XKT designed project, constructed plasmid and wrote the manuscript; BZ and JPZ supervised the whole project.
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Yang, L., Pei, Rj., Li, H. et al. Identification of SARS-CoV-2 entry inhibitors among already approved drugs. Acta Pharmacol Sin 42, 1347–1353 (2021). https://doi.org/10.1038/s41401-020-00556-6
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DOI: https://doi.org/10.1038/s41401-020-00556-6
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