6-Thioguanine blocks SARS-CoV-2 replication by inhibition of PLpro.
Autor: | Swaim CD; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA., Dwivedi V; Disease Intervention and Prevention, Texas Biomedical Research Institute, San Antonio, TX, USA., Perng YC; Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA., Zhao X; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA., Canadeo LA; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA., Harastani HH; Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA., Darling TL; Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA., Boon ACM; Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA., Lenschow DJ; Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA., Kulkarni V; Disease Intervention and Prevention, Texas Biomedical Research Institute, San Antonio, TX, USA., Huibregtse JM; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA. |
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Jazyk: | angličtina |
Zdroj: | IScience [iScience] 2021 Oct 22; Vol. 24 (10), pp. 103213. Date of Electronic Publication: 2021 Oct 02. |
DOI: | 10.1016/j.isci.2021.103213 |
Abstrakt: | The emergence of SARS-CoV-2 has led to a global health crisis that, in addition to vaccines and immunomodulatory therapies, calls for the identification of antiviral therapeutics. The papain-like protease (PLpro) activity of nsp3 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), an orally available and widely available generic drug, inhibits SARS-CoV-2 replication in Vero-E6 cells with an EC50 of approximately 2 μM. 6-TG also inhibited PLpro-catalyzed polyprotein cleavage and de-ISGylation in cells and inhibited proteolytic activity of the purified PLpro domain in vitro . We therefore propose that 6-TG is a direct-acting antiviral that could potentially be repurposed and incorporated into the set of treatment and prevention options for COVID-19. Competing Interests: Authors declare no competing interests. (© 2021 The Author(s).) |
Databáze: | MEDLINE |
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