Evidence map›Paper›PMID 35037045›Full record

ArticleNucleic acids research2022

Characterization of the SARS-CoV-2 ExoN (nsp14ExoN-nsp10) complex: implications for its role in viral genome stability and inhibitor identification.

Hannah T Baddock, Sanja Brolih, Yuliana Yosaatmadja, Malitha Ratnaweera, Marcin Bielinski, Lonnie P Swift, Abimael Cruz-Migoni, Haitian Fan, Jeremy R Keown, Alexander P Walker and 6 more

Abstract read
In one paragraph

Article in Nucleic acids research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
49citing papers in PubMed, 1 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

49 citing papers in PubMed, 1 synthesis or guideline pooled it.

  1. Pooled it
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  15. SARS-CoV-2 and the DNA damage response.The Journal of general virology · 2023
    Review
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

16 authors.

Hannah T BaddockDepartment of Oncology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
Sanja BrolihDepartment of Oncology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
Yuliana YosaatmadjaCentre for Medicines Discovery, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
Malitha RatnaweeraDepartment of Oncology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
Marcin BielinskiChemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.
Lonnie P SwiftDepartment of Oncology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
Abimael Cruz-MigoniDepartment of Oncology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
Haitian FanSir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
Jeremy R KeownDivision of Structural Biology, Henry Wellcome Building for Genomic Medicine, University of Oxford, Oxford OX3 7BN, UK.
Alexander P WalkerSir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
Garrett M MorrisDepartment of Statistics, University of Oxford, 24-29 St Giles', Oxford OX1 3LB, UK.
Jonathan M GrimesDivision of Structural Biology, Henry Wellcome Building for Genomic Medicine, University of Oxford, Oxford OX3 7BN, UK.
Ervin FodorSir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.ORCID 0000-0003-3249-196X
Christopher J SchofieldChemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.
Opher GileadiCentre for Medicines Discovery, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.ORCID 0000-0001-6886-898X
Peter J McHughDepartment of Oncology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.ORCID 0000-0002-8679-4627

Funding

Cancer Research UK 16466Cancer Research UK 24759Cancer Research UK A24759Medical Research Council MR/R009368/1Medical Research Council MR/R009945/1Wellcome Trust 106169/ZZ14/ZWellcome Trust 200835/Z/16/Z
6 · The paper itself

Abstract

The SARS-CoV-2 coronavirus is the causal agent of the current global pandemic. SARS-CoV-2 belongs to an order, Nidovirales, with very large RNA genomes. It is proposed that the fidelity of coronavirus (CoV) genome replication is aided by an RNA nuclease complex, comprising the non-structural proteins 14 and 10 (nsp14-nsp10), an attractive target for antiviral inhibition. Our results validate reports that the SARS-CoV-2 nsp14-nsp10 complex has RNase activity. Detailed functional characterization reveals nsp14-nsp10 is a versatile nuclease capable of digesting a wide variety of RNA structures, including those with a blocked 3'-terminus. Consistent with a role in maintaining viral genome integrity during replication, we find that nsp14-nsp10 activity is enhanced by the viral RNA-dependent RNA polymerase complex (RdRp) consisting of nsp12-nsp7-nsp8 (nsp12-7-8) and demonstrate that this stimulation is mediated by nsp8. We propose that the role of nsp14-nsp10 in maintaining replication fidelity goes beyond classical proofreading by purging the nascent replicating RNA strand of a range of potentially replication-terminating aberrations. Using our developed assays, we identify drug and drug-like molecules that inhibit nsp14-nsp10, including the known SARS-CoV-2 major protease (Mpro) inhibitor ebselen and the HIV integrase inhibitor raltegravir, revealing the potential for multifunctional inhibitors in COVID-19 treatment.

Indexed as

Drug Evaluation, PreclinicalGenomic InstabilityAntiviral AgentsCoronavirus RNA-Dependent RNA PolymeraseExoribonucleasesGenome, ViralHIV Integrase InhibitorsIsoindolesMultienzyme ComplexesOrganoselenium CompoundsRaltegravir PotassiumRNA, ViralSARS-CoV-2Viral Nonstructural ProteinsViral Regulatory and Accessory ProteinsVirus ReplicationAntiviral AgentsCoronavirus RNA-Dependent RNA PolymeraseebselenExoribonucleasesHIV Integrase InhibitorsIsoindolesMultienzyme ComplexesNS8 protein, SARS-CoV-2NSP12 protein, SARS-CoV-2NSP14 protein, SARS-CoV-2ORF1ab polyprotein, SARS-CoV-2Organoselenium CompoundsRaltegravir PotassiumRNA, ViralViral Nonstructural ProteinsViral Regulatory and Accessory Proteins

Identifiers

PMID35037045
PMCPMC8860572

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.