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

iScience (Oct 2021)

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

Journal volume & issue: Vol. 24, no. 10
p. 103213

Abstract

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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 in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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