The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus
Identifieur interne : 000D78 ( Pmc/Curation ); précédent : 000D77; suivant : 000D79The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus
Auteurs : Calvin J. Gordon [Canada] ; Egor P. Tchesnokov [Canada] ; Joy Y. Feng [États-Unis] ; Danielle P. Porter [États-Unis] ; Matthias Götte [Canada]Source :
- The Journal of Biological Chemistry [ 0021-9258 ] ; 2020.
Abstract
Antiviral drugs for managing infections with human coronaviruses are not yet approved, posing a serious challenge to current global efforts aimed at containing the outbreak of severe acute respiratory syndrome–coronavirus 2 (CoV-2). Remdesivir (RDV) is an investigational compound with a broad spectrum of antiviral activities against RNA viruses, including severe acute respiratory syndrome–CoV and Middle East respiratory syndrome (MERS–CoV). RDV is a nucleotide analog inhibitor of RNA-dependent RNA polymerases (RdRps). Here, we co-expressed the MERS–CoV nonstructural proteins nsp5, nsp7, nsp8, and nsp12 (RdRp) in insect cells as a part a polyprotein to study the mechanism of inhibition of MERS–CoV RdRp by RDV. We initially demonstrated that nsp8 and nsp12 form an active complex. The triphosphate form of the inhibitor (RDV-TP) competes with its natural counterpart ATP. Of note, the selectivity value for RDV-TP obtained here with a steady-state approach suggests that it is more efficiently incorporated than ATP and two other nucleotide analogs. Once incorporated at position
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DOI: 10.1074/jbc.AC120.013056
PubMed: 32094225
PubMed Central: 7152756
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Tchesnokov</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2E1</wicri:regionArea></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="2"><nlm:aff id="aff2">Gilead Sciences, Inc., Foster City, California 94404</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Gilead Sciences, Inc., Foster City</wicri:cityArea></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="2"><nlm:aff id="aff2">Gilead Sciences, Inc., Foster City, California 94404</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Gilead Sciences, Inc., Foster City</wicri:cityArea></affiliation></author><author><name sortKey="Gotte, Matthias" sort="Gotte, Matthias" uniqKey="Gotte M" first="Matthias" last="Götte">Matthias Götte</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2E1</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3">Li Ka Shing Institute of Virology at University of Alberta, Edmonton, Alberta T6G 2E1, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Li Ka Shing Institute of Virology at University of Alberta, Edmonton, Alberta T6G 2E1</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">32094225</idno><idno type="pmc">7152756</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7152756</idno><idno type="RBID">PMC:7152756</idno><idno type="doi">10.1074/jbc.AC120.013056</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">000D78</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000D78</idno><idno type="wicri:Area/Pmc/Curation">000D78</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000D78</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus</title><author><name sortKey="Gordon, Calvin J" sort="Gordon, Calvin J" uniqKey="Gordon C" first="Calvin J." last="Gordon">Calvin J. Gordon</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2E1</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:aff id="aff1">Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2E1</wicri:regionArea></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="2"><nlm:aff id="aff2">Gilead Sciences, Inc., Foster City, California 94404</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Gilead Sciences, Inc., Foster City</wicri:cityArea></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="2"><nlm:aff id="aff2">Gilead Sciences, Inc., Foster City, California 94404</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Gilead Sciences, Inc., Foster City</wicri:cityArea></affiliation></author><author><name sortKey="Gotte, Matthias" sort="Gotte, Matthias" uniqKey="Gotte M" first="Matthias" last="Götte">Matthias Götte</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2E1</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3">Li Ka Shing Institute of Virology at University of Alberta, Edmonton, Alberta T6G 2E1, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Li Ka Shing Institute of Virology at University of Alberta, Edmonton, Alberta T6G 2E1</wicri:regionArea></affiliation></author></analytic><series><title level="j">The Journal of Biological Chemistry</title><idno type="ISSN">0021-9258</idno><idno type="eISSN">1083-351X</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Antiviral drugs for managing infections with human coronaviruses are not yet approved, posing a serious challenge to current global efforts aimed at containing the outbreak of severe acute respiratory syndrome–coronavirus 2 (CoV-2). Remdesivir (RDV) is an investigational compound with a broad spectrum of antiviral activities against RNA viruses, including severe acute respiratory syndrome–CoV and Middle East respiratory syndrome (MERS–CoV). RDV is a nucleotide analog inhibitor of RNA-dependent RNA polymerases (RdRps). Here, we co-expressed the MERS–CoV nonstructural proteins nsp5, nsp7, nsp8, and nsp12 (RdRp) in insect cells as a part a polyprotein to study the mechanism of inhibition of MERS–CoV RdRp by RDV. We initially demonstrated that nsp8 and nsp12 form an active complex. The triphosphate form of the inhibitor (RDV-TP) competes with its natural counterpart ATP. Of note, the selectivity value for RDV-TP obtained here with a steady-state approach suggests that it is more efficiently incorporated than ATP and two other nucleotide analogs. Once incorporated at position <italic>i</italic>, the inhibitor caused RNA synthesis arrest at position <italic>i</italic> + 3. Hence, the likely mechanism of action is delayed RNA chain termination. The additional three nucleotides may protect the inhibitor from excision by the viral 3′–5′ exonuclease activity. Together, these results help to explain the high potency of RDV against RNA viruses in cell-based assays.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Sheahan, T P" uniqKey="Sheahan T">T. P. Sheahan</name></author><author><name sortKey="Sims, A C" uniqKey="Sims A">A. C. Sims</name></author><author><name sortKey="Leist, S R" uniqKey="Leist S">S. R. Leist</name></author><author><name sortKey="Sch Fer, A" uniqKey="Sch Fer A">A. Schäfer</name></author><author><name sortKey="Won, J" uniqKey="Won J">J. Won</name></author><author><name sortKey="Brown, A J" uniqKey="Brown A">A. J. Brown</name></author><author><name sortKey="Montgomery, S A" uniqKey="Montgomery S">S. A. Montgomery</name></author><author><name sortKey="Hogg, A" uniqKey="Hogg A">A. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">J Biol Chem</journal-id><journal-id journal-id-type="iso-abbrev">J. Biol. Chem</journal-id><journal-id journal-id-type="hwp">jbc</journal-id><journal-id journal-id-type="pmc">jbc</journal-id><journal-id journal-id-type="publisher-id">JBC</journal-id><journal-title-group><journal-title>The Journal of Biological Chemistry</journal-title></journal-title-group><issn pub-type="ppub">0021-9258</issn><issn pub-type="epub">1083-351X</issn><publisher><publisher-name>American Society for Biochemistry and Molecular Biology</publisher-name><publisher-loc>11200 Rockville Pike, Suite 302, Rockville, MD 20852-3110, U.S.A.</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">32094225</article-id><article-id pub-id-type="pmc">7152756</article-id><article-id pub-id-type="publisher-id">AC120.013056</article-id><article-id pub-id-type="doi">10.1074/jbc.AC120.013056</article-id><article-categories><subj-group subj-group-type="heading"><subject>Editors' Picks</subject></subj-group></article-categories><title-group><article-title>The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus</article-title><alt-title alt-title-type="short">EDITORS' PICK: Coronavirus polymerase inhibition with remdesivir</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Gordon</surname><given-names>Calvin J.</given-names></name><ext-link ext-link-type="uri" xlink:href="http://www.jbc.org/content/295/15/4773/suppl/DCAuthor_profile"></ext-link><xref ref-type="aff" rid="aff1"><sup>‡</sup></xref><xref ref-type="author-notes" rid="FN1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tchesnokov</surname><given-names>Egor P.</given-names></name><xref ref-type="aff" rid="aff1"><sup>‡</sup></xref><xref ref-type="author-notes" rid="FN1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Feng</surname><given-names>Joy Y.</given-names></name><xref ref-type="aff" rid="aff2"><sup>§</sup></xref></contrib><contrib contrib-type="author"><name><surname>Porter</surname><given-names>Danielle P.</given-names></name><xref ref-type="aff" rid="aff2"><sup>§</sup></xref></contrib><contrib contrib-type="author"><name><surname>Götte</surname><given-names>Matthias</given-names></name><xref ref-type="aff" rid="aff1"><sup>‡</sup></xref><xref ref-type="aff" rid="aff3"><sup>¶</sup></xref><xref ref-type="corresp" rid="cor1"><sup>2</sup></xref></contrib><aff id="aff1"><label>‡</label>Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada</aff><aff id="aff2"><label>§</label>Gilead Sciences, Inc., Foster City, California 94404</aff><aff id="aff3"><label>¶</label>Li Ka Shing Institute of Virology at University of Alberta, Edmonton, Alberta T6G 2E1, Canada</aff></contrib-group><author-notes><corresp id="cor1"><label>2</label> To whom correspondence should be addressed:
<addr-line>Dept. of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.</addr-line> Tel.:
<phone>780-492-2308</phone>; E-mail:
<email>gotte@ualberta.ca</email>.</corresp><fn fn-type="equal" id="FN1"><label>1</label><p>These authors contributed equally to this work.</p></fn><fn fn-type="edited-by"><p>Edited by Craig E. Cameron</p></fn></author-notes><pub-date pub-type="ppub"><day>10</day><month>4</month><year>2020</year></pub-date><pub-date pub-type="epub"><day>24</day><month>2</month><year>2020</year></pub-date><pub-date pub-type="pmc-release"><day>24</day><month>2</month><year>2020</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
<volume>295</volume><issue>15</issue><fpage>4773</fpage><lpage>4779</lpage><history><date date-type="received"><day>14</day><month>2</month><year>2020</year></date><date date-type="rev-recd"><day>19</day><month>2</month><year>2020</year></date></history><permissions><copyright-statement>© 2020 Gordon et al.</copyright-statement><copyright-year>2020</copyright-year><copyright-holder>Gordon et al.</copyright-holder><license><license-p>Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="zbc01520004773.pdf"></self-uri><abstract><p>Antiviral drugs for managing infections with human coronaviruses are not yet approved, posing a serious challenge to current global efforts aimed at containing the outbreak of severe acute respiratory syndrome–coronavirus 2 (CoV-2). Remdesivir (RDV) is an investigational compound with a broad spectrum of antiviral activities against RNA viruses, including severe acute respiratory syndrome–CoV and Middle East respiratory syndrome (MERS–CoV). RDV is a nucleotide analog inhibitor of RNA-dependent RNA polymerases (RdRps). Here, we co-expressed the MERS–CoV nonstructural proteins nsp5, nsp7, nsp8, and nsp12 (RdRp) in insect cells as a part a polyprotein to study the mechanism of inhibition of MERS–CoV RdRp by RDV. We initially demonstrated that nsp8 and nsp12 form an active complex. The triphosphate form of the inhibitor (RDV-TP) competes with its natural counterpart ATP. Of note, the selectivity value for RDV-TP obtained here with a steady-state approach suggests that it is more efficiently incorporated than ATP and two other nucleotide analogs. Once incorporated at position <italic>i</italic>, the inhibitor caused RNA synthesis arrest at position <italic>i</italic> + 3. Hence, the likely mechanism of action is delayed RNA chain termination. The additional three nucleotides may protect the inhibitor from excision by the viral 3′–5′ exonuclease activity. Together, these results help to explain the high potency of RDV against RNA viruses in cell-based assays.</p></abstract><kwd-group><kwd>plus-stranded RNA virus</kwd><kwd>viral polymerase</kwd><kwd>drug development</kwd><kwd>enzyme inhibitor</kwd><kwd>nucleoside/nucleotide analog</kwd><kwd>coronavirus</kwd><kwd>positive-sense RNA virus</kwd><kwd>Ebola virus (EBOV)</kwd><kwd>Middle East respiratory syndrome coronavirus (MERS–CoV)</kwd><kwd>SARS–CoV-2</kwd><kwd>remdesivir</kwd><kwd>antiviral drug</kwd><kwd>RNA chain termination</kwd><kwd>RNA-dependent RNA polymerase (RdRp)</kwd><kwd>viral replicase</kwd></kwd-group><funding-group><award-group id="award1"><funding-source><institution-wrap><institution>Gouvernement du Canada | Canadian Institutes of Health Research (CIHR)
</institution><institution-id institution-id-type="open-funder-registry">10.13039/501100000024</institution-id></institution-wrap></funding-source><award-id>159507</award-id><principal-award-recipient><name><surname>Götte</surname><given-names>Matthias</given-names></name></principal-award-recipient></award-group><award-group id="award2"><funding-source>Alberta Ministry of Economic Development, Trade, and Tourism by the Major Innovation Fund Program</funding-source><award-id>AMR-One Health Consortium</award-id><principal-award-recipient><name><surname>Götte</surname><given-names>Matthias</given-names></name></principal-award-recipient></award-group></funding-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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