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

被引：28
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
收藏
页数：12
相关论文
共 23 条
  • [1] Hepatitis C virus drugs that inhibit SARS-CoV-2 papain-like protease synergize with remdesivir to suppress viral replication in cell culture
    Bafna, Khushboo
    White, Kris
    Harish, Balasubramanian
    Rosales, Romel
    Ramelot, Theresa A.
    Acton, Thomas B.
    Moreno, Elena
    Kehrer, Thomas
    Miorin, Lisa
    Royer, Catherine A.
    Garcia-Sastre, Adolfo
    Krug, Robert M.
    Montelione, Gaetano T.
    [J]. CELL REPORTS, 2021, 35 (07):
  • [2] The continuous rediscovery and the benefit-risk ratio of thioguanine, a comprehensive review
    Bayoumy, Ahmed B.
    Simsek, Melek
    Seinen, Margien L.
    Mulder, Chris J. J.
    Ansari, Azhar
    Peters, Godefridus J.
    De Boer, Nanne K.
    [J]. EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY, 2020, 16 (02) : 111 - 123
  • [3] Thiopurine analogs and mycophenolic acid synergistically inhibit the papain-like protease of Middle East respiratory syndrome coronavirus
    Cheng, Kai-Wen
    Cheng, Shu-Chun
    Chen, Wei-Yi
    Lin, Min-Han
    Chuang, Shang-Ju
    Cheng, I-Hsin
    Sun, Chiao-Yin
    Chou, Chi-Yuan
    [J]. ANTIVIRAL RESEARCH, 2015, 115 : 9 - 16
  • [4] Thiopurine analogues inhibit papain-like protease of severe acute respiratory syndrome coronavirus
    Chou, Chi-Yuan
    Chien, Chia-Hui
    Han, Yu-San
    Prebanda, Mojca Trstenjak
    Hsieh, Hsing-Pang
    Turk, Boris
    Chang, Gu-Gang
    Chen, Xin
    [J]. BIOCHEMICAL PHARMACOLOGY, 2008, 75 (08) : 1601 - 1609
  • [5] Structurally Guided Removal of DeISGylase Biochemical Activity from Papain-Like Protease Originating from Middle East Respiratory Syndrome Coronavirus
    Daczkowski, Courtney M.
    Goodwin, Octavia Y.
    Dzimianski, John V.
    Farhat, Jonathan J.
    Pegan, Scott D.
    [J]. JOURNAL OF VIROLOGY, 2017, 91 (23)
  • [6] Herc5, an interferon-induced HECT E3 enzyme, is required for conjugation of ISG15 in human cells
    Dastur, A
    Beaudenon, S
    Kelley, M
    Krug, RM
    Huibregtse, JM
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 (07) : 4334 - 4338
  • [7] The basis for selective E1-E2 interactions in the ISG15 conjugation system
    Durfee, Larissa A.
    Kelley, Melissa L.
    Huibregtse, Jon M.
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283 (35) : 23895 - 23902
  • [8] The ISG15 Conjugation System Broadly Targets Newly Synthesized Proteins: Implications for the Antiviral Function of ISG15
    Durfee, Larissa A.
    Lyon, Nancy
    Seo, Kyungwoon
    Huibregtse, Jon M.
    [J]. MOLECULAR CELL, 2010, 38 (05) : 722 - 732
  • [9] Characterization and Noncovalent Inhibition of the Deubiquitinase and delSGylase Activity of SARS-CoV-2 Papain-Like Protease
    Freitas, Brendan T.
    Durie, Ian A.
    Murray, Jackelyn
    Longo, Jaron E.
    Miller, Holden C.
    Crich, David
    Hogan, Robert Jeff
    Tripp, Ralph A.
    Pegan, Scott D.
    [J]. ACS INFECTIOUS DISEASES, 2020, 6 (08): : 2099 - 2109
  • [10] The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2
    Gorbalenya, Alexander E.
    Baker, Susan C.
    Baric, Ralph S.
    de Groot, Raoul J.
    Drosten, Christian
    Gulyaeva, Anastasia A.
    Haagmans, Bart L.
    Lauber, Chris
    Leontovich, Andrey M.
    Neuman, Benjamin W.
    Penzar, Dmitry
    Perlman, Stanley
    Poon, Leo L. M.
    Samborskiy, Dmitry V.
    Sidorov, Igor A.
    Sola, Isabel
    Ziebuhr, John
    [J]. NATURE MICROBIOLOGY, 2020, 5 (04) : 536 - 544
123