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

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, Jon M. Huibregtse

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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.

Original languageEnglish
Article number103213
Issue number10
StatePublished - Oct 22 2021


  • Drugs
  • Therapeutics
  • Virology


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