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
Affiliations
Caleb D. Swaim
Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA
Varun Dwivedi
Disease Intervention and Prevention, Texas Biomedical Research Institute, San Antonio, TX, USA
Yi-Chieh Perng
Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
Xu Zhao
Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA
Larissa A. Canadeo
Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA
Houda H. Harastani
Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
Tamarand L. Darling
Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
Adrianus C.M. Boon
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
Deborah J. Lenschow
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
Viraj Kulkarni
Disease Intervention and Prevention, Texas Biomedical Research Institute, San Antonio, TX, USA
Jon M. Huibregtse
Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA; Corresponding author
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.
