Swaim Caleb D, Dwivedi Varun, Perng Yi-Chieh, Zhao Xu, Canadeo Larissa A, Harastani Houda H, Darling Tamarand L, Boon Adrianus C M, Lenschow Deborah J, Kulkarni Viraj, Huibregtse Jon M
Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA.
Disease Intervention and Prevention, Texas Biomedical Research Institute, San Antonio, TX, USA.
iScience. 2021 Oct 22;24(10):103213. doi: 10.1016/j.isci.2021.103213. Epub 2021 Oct 2.
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 . 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.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的出现引发了一场全球健康危机，除了疫苗和免疫调节疗法外，还需要鉴定抗病毒治疗药物。非结构蛋白3（nsp3）的木瓜蛋白酶样蛋白酶（PLpro）活性是一个有吸引力的药物靶点，因为它对于病毒多聚蛋白切割以及抗病毒泛素样蛋白ISG15的去共轭化至关重要。我们在此表明，6-硫鸟嘌呤（6-TG）是一种口服可用且广泛可得的非专利药物，在Vero-E6细胞中抑制SARS-CoV-2复制，其半数有效浓度（EC50）约为2μM。6-TG还抑制细胞中PLpro催化的多聚蛋白切割和去ISGylation，并抑制纯化的PLpro结构域的蛋白水解活性。因此，我们提出6-TG是一种直接作用的抗病毒药物，有可能被重新利用并纳入COVID-19的治疗和预防方案中。
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