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

被引：31

作者：

Swaim, Caleb D. ^{[1
]}

Dwivedi, Varun ^{[2
]}

Perng, Yi-Chieh ^{[3
]}

Zhao, Xu ^{[1
]}

Canadeo, Larissa A. ^{[1
]}

Harastani, Houda H. ^{[3
]}

Darling, Tamarand L. ^{[3
]}

Boon, Adrianus C. M. ^{[3
,4
,5
]}

Lenschow, Deborah J. ^{[3
,4
]}

Kulkarni, Viraj ^{[2
]}

Huibregtse, Jon M. ^{[1
]}

机构：

[1] Univ Texas Austin, Dept Mol Biosci, Austin, TX 78712 USA

[2] Texas Biomed Res Inst, Dis Intervent & Prevent, San Antonio, TX USA

[3] Washington Univ, Sch Med, Dept Internal Med, St Louis, MO 63110 USA

[4] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA

[5] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA

来源：

ISCIENCE | 2021年 / 24卷 / 09期

基金：

美国国家卫生研究院;

关键词：

PAPAIN-LIKE PROTEASE; INFLAMMATORY-BOWEL-DISEASE; THIOPURINE ANALOGS; CONJUGATION; ISG15;

D O I：

10.1016/j.isci.2021.103213

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 mu M. 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.

引用

页数：12

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