1. 6-Thioguanine blocks SARS-CoV-2 replication by inhibition of PLpro
- Author
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Caleb D. Swaim, Varun Dwivedi, Yi-Chieh Perng, Xu Zhao, Larissa A. Canadeo, Houda H. Harastani, Tamarand L. Darling, Adrianus C.M. Boon, Deborah J. Lenschow, Viraj Kulkarni, and Jon M. Huibregtse
- Subjects
Therapeutics ,Drugs ,Virology ,Science - Abstract
Summary: 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.
- Published
- 2021
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