Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp14/nsp10 exoribonuclease

被引：32

作者：

Canal, Berta ^{[1
]}

McClure, Allison W. ^{[1
]}

Curran, Joseph F. ^{[2
]}

Wu, Mary ^{[4
]}

Ulferts, Rachel ^{[3
]}

Weissmann, Florian ^{[1
]}

Zeng, Jingkun ^{[1
]}

Bertolin, Agustina P. ^{[1
]}

Milligan, Jennifer C. ^{[1
]}

Basu, Souradeep ^{[2
]}

Drury, Lucy S. ^{[1
]}

Deegan, Tom D. ^{[5
]}

Fujisawa, Ryo ^{[5
]}

Roberts, Emma L. ^{[2
]}

Basier, Clovis ^{[2
]}

Labib, Karim ^{[5
]}

Beale, Rupert ^{[3
]}

Howell, Michael ^{[4
]}

Diffley, John F. X. ^{[1
]}

机构：

[1] Francis Crick Inst, Chromosome Replicat Lab, 1 Midland Rd, London NW1 1AT, England

[2] Francis Crick Inst, Cell Cycle Lab, 1 Midland Rd, London NW1 1AT, England

[3] Francis Crick Inst, Cell Biol Infect Lab, 1 Midland Rd, London NW1 1AT, England

[4] Francis Crick Inst, High Throughput Screening, 1 Midland Rd, London NW1 1AT, England

[5] Univ Dundee, Sch Life Sci, MRC Prot Phosphorylat & Ubiquitylat Unit, Dundee DD1 5EH, Scotland

来源：

BIOCHEMICAL JOURNAL | 2021年 / 478卷 / 01期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

AURINTRICARBOXYLIC ACID; SELECTIVE-INHIBITION; VIRUS-REPLICATION; RNA VIRUS; CORONAVIRUS; PROTEIN; COMPLEX; PATULIN; NSP14; POLYMERASE;

D O I：

10.1042/BCJ20210198

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

SARS-CoV-2 is a coronavirus that emerged in 2019 and rapidly spread across the world causing a deadly pandemic with tremendous social and economic costs. Healthcare systems worldwide are under great pressure, and there is an urgent need for effective antiviral treatments. The only currently approved antiviral treatment for COVID-19 is remdesivir, an inhibitor of viral genome replication. SARS-CoV-2 proliferation relies on the enzymatic activities of the non-structural proteins (nsp), which makes them interesting targets for the development of new antiviral treatments. With the aim to identify novel SARS-CoV-2 antivirals, we have purified the exoribonuclease/methyltransferase (nsp14) and its cofactor (nsp10) and developed biochemical assays compatible with highthroughput approaches to screen for exoribonuclease inhibitors. We have screened a library of over 5000 commercial compounds and identified patulin and aurintricarboxylic acid (ATA) as inhibitors of nsp14 exoribonuclease in vitro. We found that patulin and ATA inhibit replication of SARS-CoV-2 in a VERO E6 cell-culture model. These two new antiviral compounds will be valuable tools for further coronavirus research as well as potentially contributing to new therapeutic opportunities for COVID-19.

引用

页码：2445 / 2464

页数：20

共 76 条

[41] Discovery of an RNA virus 3′→5′ exoribonuclease that is critically involved in coronavirus RNA synthesis [J].

Minskaia, E ;

Hertzig, T ;

Gorbalenya, AE ;

Campanacci, V ;

Cambillau, C ;

Canard, B ;

Ziebuhr, J .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (13) :5108-5113

[42] The proofreading domain of Escherichia coli DNA polymerase I and other DNA and/or RNA exonuclease domains [J].

Moser, MJ ;

Holley, WR ;

Chatterjee, A ;

Mian, IS .

NUCLEIC ACIDS RESEARCH, 1997, 25 (24) :5110-5118

[43] The Enzymatic Activity of the nsp14 Exoribonuclease Is Critical for Replication of MERS-CoV and SARS-CoV-2 [J].

Ogando, Natacha S. ;

Zevenhoven-Dobbe, Jessika C. ;

van der Meer, Yvonne ;

Bredenbeek, Peter J. ;

Posthuma, Clara C. ;

Snijder, Eric J. .

JOURNAL OF VIROLOGY, 2020, 94 (23)

[44] The Curious Case of the Nidovirus Exoribonuclease: Its Role in RNA Synthesis and Replication Fidelity [J].

Ogando, Natacha S. ;

Ferron, Francois ;

Decroly, Etienne ;

Canard, Bruno ;

Posthuma, Clara C. ;

Snijder, Eric J. .

FRONTIERS IN MICROBIOLOGY, 2019, 10

[45] Repurposed Antiviral Drugs for Covid-19-Interim WHO Solidarity Trial Results [J].

Pan, Hongchao ;

Peto, Richard ;

Karim, Quarraisha Abdool ;

Alejandria, Marissa ;

Henao-Restrepo, Ana Maria ;

Garcia, Cesar Hernandez ;

Kieny, Marie Paule ;

Malekzadeh, Reza ;

Murthy, Srinivas ;

Preziosi, Marie-Pierre ;

Reddy, K. Srinath ;

Periago, Mirta Roses ;

Sathiyamoorthy, Vasee ;

Rottingen, John-Arne ;

Swaminathan, Soumya ;

Maggioni, Aldo ;

Babiker, Abdel ;

Cook, Deborah ;

Dondorp, Arjen ;

Kang, Gagandeep ;

Trelle, S. ;

McGinty, S. ;

Branca, M. ;

Appadoo, S. ;

Sterne, J. A. C. ;

Rogers, C. A. ;

Cappel-Porter, H. B. C. ;

Hutton, D. ;

Bellani, S. ;

Allum, E. ;

Kirwan, J. ;

Lydon, P. ;

Miranda-Montoya, M. C. ;

Salami, K. K. ;

Sathiyamoorthy, V. ;

Swaminathan, S. ;

Como, N. ;

Sinani, N. ;

Lopardo, G. ;

Periago, M. Roses ;

Nunes, E. P. ;

Reges, P. P. S. ;

Murthy, S. ;

Salvadori, M. ;

Alvarez-Moreno, C. A. ;

Rubio, M. L. Mesa ;

Hassany, M. ;

Zaid, H. ;

Tikkinen, K. A. O. ;

Perola, M. .

NEW ENGLAND JOURNAL OF MEDICINE, 2021, 384 (06) :497-511

[46] Potent Inhibition of Zika Virus Replication by Aurintricarboxylic Acid [J].

Park, Jun-Gyu ;

Avila-Perez, Gines ;

Madere, Ferralita ;

Hilimire, Thomas A. ;

Nogales, Aitor ;

Almazan, Fernando ;

Martinez-Sobrido, Luis .

FRONTIERS IN MICROBIOLOGY, 2019, 10

[47] Coronavirus as a possible cause of severe acute respiratory syndrome [J].

Peiris, JSM ;

Lai, ST ;

Poon, LLM ;

Guan, Y ;

Yam, LYC ;

Lim, W ;

Nicholls, J ;

Yee, WKS ;

Yan, WW ;

Cheung, MT ;

Cheng, VCC ;

Chan, KH ;

Tsang, DNC ;

Yung, RWH ;

Ng, TK ;

Yuen, KY .

LANCET, 2003, 361 (9366) :1319-1325

[48] Biosynthesis and Toxicological Effects of Patulin [J].

Puel, Olivier ;

Galtier, Pierre ;

Oswald, Isabelle P. .

TOXINS, 2010, 2 (04) :613-631

[49] Coronavirus RNA Proofreading: Molecular Basis and Therapeutic Targeting [J].

Robson, Fran ;

Khan, Khadija Shahed ;

Le, Thi Khanh ;

Paris, Clement ;

Demirbag, Sinem ;

Barfuss, Peter ;

Rocchi, Palma ;

Ng, Wai-Lung .

MOLECULAR CELL, 2020, 79 (05) :710-727

[50] New targets for drug design: importance of nsp14/nsp10 complex formation for the 3'-5' exoribonucleolytic activity on SARS-CoV-2 [J].

Saramago, Margarida ;

Barria, Catia ;

Costa, Vanessa G. ;

Souza, Caio S. ;

Viegas, Sandra C. ;

Domingues, Susana ;

Lousa, Diana ;

Soares, Claudio M. ;

Arraiano, Cecilia M. ;

Matos, Rute G. .

FEBS JOURNAL, 2021, 288 (17) :5130-5147

← 1 2 3 4 5 6 7 8 →