Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency.
Identifieur interne : 003941 ( Ncbi/Merge ); précédent : 003940; suivant : 003942Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency.
Auteurs : Calvin J. Gordon [Canada] ; Egor P. Tchesnokov [Canada] ; Emma Woolner [Canada] ; Jason K. Perry [États-Unis] ; Joy Y. Feng [États-Unis] ; Danielle P. Porter [États-Unis] ; Matthias Gotte [Canada]Source :
- The Journal of biological chemistry [ 1083-351X ] ; 2020.
Abstract
Effective treatments for coronavirus disease 2019 (COVID-19) are urgently needed to control this current pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Replication of SARS-CoV-2 depends on the viral RNA-dependent RNA polymerase (RdRp), which is the likely target of the investigational nucleotide analogue remdesivir (RDV). RDV shows broad-spectrum antiviral activity against RNA viruses, and previous studies with RdRps from Ebola virus (EBOV) and Middle East respiratory syndrome coronavirus (MERS-CoV) have revealed that delayed chain-termination is RDV's plausible mechanism of action. Here, we expressed and purified active SARS-CoV-2 RdRp composed of the non-structural proteins nsp8 and nsp12. Enzyme kinetics indicated that this RdRp efficiently incorporates the active triphosphate form of RDV (RDV-TP) into RNA. Incorporation of RDV-TP at position i caused termination of RNA synthesis at position i+3. We obtained almost identical results with SARS-CoV, MERS-CoV, and SARS-CoV-2 RdRps. A unique property of RDV-TP is its high selectivity over incorporation of its natural nucleotide counterpart ATP. In this regard, the triphosphate forms of 2'-C-methylated compounds, including sofosbuvir, approved for the management of hepatitis C virus infection, and the broad-acting antivirals favipiravir and ribavirin, exhibited significant deficits. Furthermore, we provide evidence for the target specificity of RDV, as RDV-TP was less efficiently incorporated by the distantly related Lassa virus RdRp, and termination of RNA synthesis was not observed. These results collectively provide a unifying, refined mechanism of RDV-mediated RNA synthesis inhibition in coronaviruses and define this nucleotide analogue as a direct-acting antiviral (DAA).
DOI: 10.1074/jbc.RA120.013679
PubMed: 32284326
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Gordon</name><affiliation wicri:level="1"><nlm:affiliation>University of Alberta, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>University of Alberta</wicri:regionArea></affiliation></author><author><name sortKey="Tchesnokov, Egor P" sort="Tchesnokov, Egor P" uniqKey="Tchesnokov E" first="Egor P" last="Tchesnokov">Egor P. Tchesnokov</name><affiliation wicri:level="1"><nlm:affiliation>University of Alberta, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>University of Alberta</wicri:regionArea></affiliation></author><author><name sortKey="Woolner, Emma" sort="Woolner, Emma" uniqKey="Woolner E" first="Emma" last="Woolner">Emma Woolner</name><affiliation wicri:level="1"><nlm:affiliation>University of Alberta, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>University of Alberta</wicri:regionArea></affiliation></author><author><name sortKey="Perry, Jason K" sort="Perry, Jason K" uniqKey="Perry J" first="Jason K" last="Perry">Jason K. Perry</name><affiliation wicri:level="1"><nlm:affiliation>Gilead Sciences, Inc, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Gilead Sciences, Inc</wicri:regionArea><wicri:noRegion>Inc</wicri:noRegion></affiliation></author><author><name sortKey="Feng, Joy Y" sort="Feng, Joy Y" uniqKey="Feng J" first="Joy Y" last="Feng">Joy Y. Feng</name><affiliation wicri:level="1"><nlm:affiliation>Biology, Gilead Sciences, Inc., United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Biology, Gilead Sciences, Inc.</wicri:regionArea><wicri:noRegion>Inc.</wicri:noRegion></affiliation></author><author><name sortKey="Porter, Danielle P" sort="Porter, Danielle P" uniqKey="Porter D" first="Danielle P" last="Porter">Danielle P. Porter</name><affiliation wicri:level="1"><nlm:affiliation>Gilead Scienes, Inc., United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Gilead Scienes, Inc.</wicri:regionArea><wicri:noRegion>Inc.</wicri:noRegion></affiliation></author><author><name sortKey="Gotte, Matthias" sort="Gotte, Matthias" uniqKey="Gotte M" first="Matthias" last="Gotte">Matthias Gotte</name><affiliation wicri:level="1"><nlm:affiliation>Medical Microbiology and Immunology, University of Alberta, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Medical Microbiology and Immunology, University of Alberta</wicri:regionArea><wicri:noRegion>University of Alberta</wicri:noRegion></affiliation></author></analytic><series><title level="j">The Journal of biological chemistry</title><idno type="eISSN">1083-351X</idno><imprint><date when="2020" type="published">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Effective treatments for coronavirus disease 2019 (COVID-19) are urgently needed to control this current pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Replication of SARS-CoV-2 depends on the viral RNA-dependent RNA polymerase (RdRp), which is the likely target of the investigational nucleotide analogue remdesivir (RDV). RDV shows broad-spectrum antiviral activity against RNA viruses, and previous studies with RdRps from Ebola virus (EBOV) and Middle East respiratory syndrome coronavirus (MERS-CoV) have revealed that delayed chain-termination is RDV's plausible mechanism of action. Here, we expressed and purified active SARS-CoV-2 RdRp composed of the non-structural proteins nsp8 and nsp12. Enzyme kinetics indicated that this RdRp efficiently incorporates the active triphosphate form of RDV (RDV-TP) into RNA. Incorporation of RDV-TP at position i caused termination of RNA synthesis at position i+3. We obtained almost identical results with SARS-CoV, MERS-CoV, and SARS-CoV-2 RdRps. A unique property of RDV-TP is its high selectivity over incorporation of its natural nucleotide counterpart ATP. In this regard, the triphosphate forms of 2'-C-methylated compounds, including sofosbuvir, approved for the management of hepatitis C virus infection, and the broad-acting antivirals favipiravir and ribavirin, exhibited significant deficits. Furthermore, we provide evidence for the target specificity of RDV, as RDV-TP was less efficiently incorporated by the distantly related Lassa virus RdRp, and termination of RNA synthesis was not observed. These results collectively provide a unifying, refined mechanism of RDV-mediated RNA synthesis inhibition in coronaviruses and define this nucleotide analogue as a direct-acting antiviral (DAA).</div></front></TEI><pubmed><MedlineCitation Status="Publisher" Owner="NLM"><PMID Version="1">32284326</PMID><DateRevised><Year>2020</Year><Month>04</Month><Day>16</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1083-351X</ISSN><JournalIssue CitedMedium="Internet"><PubDate><Year>2020</Year><Month>Apr</Month><Day>13</Day></PubDate></JournalIssue><Title>The Journal of biological chemistry</Title><ISOAbbreviation>J. Biol. Chem.</ISOAbbreviation></Journal><ArticleTitle>Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency.</ArticleTitle><ELocationID EIdType="pii" ValidYN="Y">jbc.RA120.013679</ELocationID><ELocationID EIdType="doi" ValidYN="Y">10.1074/jbc.RA120.013679</ELocationID><Abstract><AbstractText>Effective treatments for coronavirus disease 2019 (COVID-19) are urgently needed to control this current pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Replication of SARS-CoV-2 depends on the viral RNA-dependent RNA polymerase (RdRp), which is the likely target of the investigational nucleotide analogue remdesivir (RDV). RDV shows broad-spectrum antiviral activity against RNA viruses, and previous studies with RdRps from Ebola virus (EBOV) and Middle East respiratory syndrome coronavirus (MERS-CoV) have revealed that delayed chain-termination is RDV's plausible mechanism of action. Here, we expressed and purified active SARS-CoV-2 RdRp composed of the non-structural proteins nsp8 and nsp12. Enzyme kinetics indicated that this RdRp efficiently incorporates the active triphosphate form of RDV (RDV-TP) into RNA. Incorporation of RDV-TP at position i caused termination of RNA synthesis at position i+3. We obtained almost identical results with SARS-CoV, MERS-CoV, and SARS-CoV-2 RdRps. A unique property of RDV-TP is its high selectivity over incorporation of its natural nucleotide counterpart ATP. In this regard, the triphosphate forms of 2'-C-methylated compounds, including sofosbuvir, approved for the management of hepatitis C virus infection, and the broad-acting antivirals favipiravir and ribavirin, exhibited significant deficits. Furthermore, we provide evidence for the target specificity of RDV, as RDV-TP was less efficiently incorporated by the distantly related Lassa virus RdRp, and termination of RNA synthesis was not observed. These results collectively provide a unifying, refined mechanism of RDV-mediated RNA synthesis inhibition in coronaviruses and define this nucleotide analogue as a direct-acting antiviral (DAA).</AbstractText><CopyrightInformation>Published under license by The American Society for Biochemistry and Molecular Biology, Inc.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Gordon</LastName><ForeName>Calvin J</ForeName><Initials>CJ</Initials><AffiliationInfo><Affiliation>University of Alberta, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tchesnokov</LastName><ForeName>Egor P</ForeName><Initials>EP</Initials><Identifier Source="ORCID">https://orcid.org/0000-0003-1698-2961</Identifier><AffiliationInfo><Affiliation>University of Alberta, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Woolner</LastName><ForeName>Emma</ForeName><Initials>E</Initials><Identifier Source="ORCID">https://orcid.org/0000-0002-8697-7802</Identifier><AffiliationInfo><Affiliation>University of Alberta, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Perry</LastName><ForeName>Jason K</ForeName><Initials>JK</Initials><Identifier Source="ORCID">https://orcid.org/0000-0001-5492-0652</Identifier><AffiliationInfo><Affiliation>Gilead Sciences, Inc, United States.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Feng</LastName><ForeName>Joy Y</ForeName><Initials>JY</Initials><AffiliationInfo><Affiliation>Biology, Gilead Sciences, Inc., United States.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Porter</LastName><ForeName>Danielle P</ForeName><Initials>DP</Initials><AffiliationInfo><Affiliation>Gilead Scienes, Inc., United States.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gotte</LastName><ForeName>Matthias</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Medical Microbiology and Immunology, University of Alberta, Canada.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2020</Year><Month>04</Month><Day>13</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>J Biol Chem</MedlineTA><NlmUniqueID>2985121R</NlmUniqueID><ISSNLinking>0021-9258</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">RNA polymerase</Keyword><Keyword MajorTopicYN="N">drug action</Keyword><Keyword MajorTopicYN="N">drug development</Keyword><Keyword MajorTopicYN="N">drug discovery</Keyword><Keyword MajorTopicYN="N">plus-stranded RNA virus</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="accepted"><Year>2020</Year><Month>04</Month><Day>13</Day></PubMedPubDate><PubMedPubDate PubStatus="received"><Year>2020</Year><Month>03</Month><Day>30</Day></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2020</Year><Month>4</Month><Day>15</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2020</Year><Month>4</Month><Day>15</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2020</Year><Month>4</Month><Day>15</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>aheadofprint</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">32284326</ArticleId><ArticleId IdType="pii">RA120.013679</ArticleId><ArticleId IdType="doi">10.1074/jbc.RA120.013679</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>Canada</li><li>États-Unis</li></country></list><tree><country name="Canada"><noRegion><name sortKey="Gordon, Calvin J" sort="Gordon, Calvin J" uniqKey="Gordon C" first="Calvin J" last="Gordon">Calvin J. Gordon</name></noRegion><name sortKey="Gotte, Matthias" sort="Gotte, Matthias" uniqKey="Gotte M" first="Matthias" last="Gotte">Matthias Gotte</name><name sortKey="Tchesnokov, Egor P" sort="Tchesnokov, Egor P" uniqKey="Tchesnokov E" first="Egor P" last="Tchesnokov">Egor P. Tchesnokov</name><name sortKey="Woolner, Emma" sort="Woolner, Emma" uniqKey="Woolner E" first="Emma" last="Woolner">Emma Woolner</name></country><country name="États-Unis"><noRegion><name sortKey="Perry, Jason K" sort="Perry, Jason K" uniqKey="Perry J" first="Jason K" last="Perry">Jason K. Perry</name></noRegion><name sortKey="Feng, Joy Y" sort="Feng, Joy Y" uniqKey="Feng J" first="Joy Y" last="Feng">Joy Y. Feng</name><name sortKey="Porter, Danielle P" sort="Porter, Danielle P" uniqKey="Porter D" first="Danielle P" last="Porter">Danielle P. Porter</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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