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

doi:10.1016/j.isci.2021.103213

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

iScience. 2021 Oct 22;24(10):103213. doi: 10.1016/j.isci.2021.103213. Epub 2021 Oct 2.

Authors

Affiliations

¹ Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA.
² Disease Intervention and Prevention, Texas Biomedical Research Institute, San Antonio, TX, USA.
³ Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.
⁴ Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
⁵ Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA.

Abstract

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.

Keywords: Drugs; Therapeutics; Virology.

Abstract

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