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bioRxiv · 10.1101/2020.07.01.183020

6-Thioguanine blocks SARS-CoV-2 replication by inhibition of PLpro protease activities

Swaim, C. D.·Perng, Y.-C.·Zhao, X.·Canadeo, L. A.·Harastani, H. H.·Darling, T. L.·Boon, A. C. M.·Lenschow, D. J.·Huibregtse, J. M.
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Abstract

A recently emerged betacoronavirus, SARS-CoV-2, has led to a global health crisis that calls for the identification of effective therapeutics for COVID-19 disease. Coronavirus papain-like protease (PLpro) is an attractive drug target as it is essential for viral polyprotein cleavage and for deconjugation of ISG15, an antiviral ubiquitin-like protein. We show here that 6-Thioguanine (6-TG) inhibits SARS-CoV-2 PLpro-catalyzed viral polyprotein cleavage and ISG15 deconjugation in cells and inhibits replication of SARS-CoV-2 in Vero-E6 cells and Calu3 cells at submicromolar levels. As a well-characterized FDA-approved orally delivered drug, 6-TG represents a promising therapeutic for COVID-19 and other emerging coronaviruses.One Sentence Summary A repurposed drug that targets an essential enzymatic activity of SARS-CoV-2 represents a promising COVID-19 therapeutic.Competing Interest StatementThe authors have declared no competing interest.View Full Text

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Swaim, C. D., Perng, Y.-C., Zhao, X., Canadeo, L. A., Harastani, H. H., Darling, T. L., Boon, A. C. M., Lenschow, D. J., Huibregtse, J. M.. 2020-07-02. 6-Thioguanine blocks SARS-CoV-2 replication by inhibition of PLpro protease activities. https://doi.org/10.1101/2020.07.01.183020

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