Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV
Identifieur interne : 000410 ( Pmc/Curation ); précédent : 000409; suivant : 000411Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV
Auteurs : Timothy P. Sheahan [États-Unis] ; Amy C. Sims [États-Unis] ; Sarah R. Leist [États-Unis] ; Alexandra Sch Fer [États-Unis] ; John Won [États-Unis] ; Ariane J. Brown [États-Unis] ; Stephanie A. Montgomery [États-Unis] ; Alison Hogg [États-Unis] ; Darius Babusis [États-Unis] ; Michael O. Clarke [États-Unis] ; Jamie E. Spahn [États-Unis] ; Laura Bauer [États-Unis] ; Scott Sellers [États-Unis] ; Danielle Porter [États-Unis] ; Joy Y. Feng [États-Unis] ; Tomas Cihlar [États-Unis] ; Robert Jordan [États-Unis] ; Mark R. Denison [États-Unis] ; Ralph S. Baric [États-Unis]Source :
- Nature Communications [ 2041-1723 ] ; 2020.
Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) is the causative agent of a severe respiratory disease associated with more than 2468 human infections and over 851 deaths in 27 countries since 2012. There are no approved treatments for MERS-CoV infection although a combination of lopinavir, ritonavir and interferon beta (LPV/RTV-IFNb) is currently being evaluated in humans in the Kingdom of Saudi Arabia. Here, we show that remdesivir (RDV) and IFNb have superior antiviral activity to LPV and RTV in vitro. In mice, both prophylactic and therapeutic RDV improve pulmonary function and reduce lung viral loads and severe lung pathology. In contrast, prophylactic LPV/RTV-IFNb slightly reduces viral loads without impacting other disease parameters. Therapeutic LPV/RTV-IFNb improves pulmonary function but does not reduce virus replication or severe lung pathology. Thus, we provide in vivo evidence of the potential for RDV to treat MERS-CoV infections.
Url:
DOI: 10.1038/s41467-019-13940-6
PubMed: 31924756
PubMed Central: 6954302
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Sheahan</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000000122483208</institution-id><institution-id institution-id-type="GRID">grid.10698.36</institution-id><institution>Department of Epidemiology,</institution><institution>University of North Carolina at Chapel Hill,</institution></institution-wrap>Chapel Hill, NC USA</nlm:aff><country>États-Unis</country><placeName><region type="state">Caroline du Nord</region></placeName><wicri:cityArea>Chapel Hill</wicri:cityArea></affiliation></author><author><name sortKey="Sims, Amy C" sort="Sims, Amy C" uniqKey="Sims A" first="Amy C." last="Sims">Amy C. Sims</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000000122483208</institution-id><institution-id institution-id-type="GRID">grid.10698.36</institution-id><institution>Department of Epidemiology,</institution><institution>University of North Carolina at Chapel Hill,</institution></institution-wrap>Chapel Hill, NC USA</nlm:aff><country>États-Unis</country><placeName><region type="state">Caroline du Nord</region></placeName><wicri:cityArea>Chapel Hill</wicri:cityArea></affiliation></author><author><name sortKey="Leist, Sarah R" sort="Leist, Sarah R" uniqKey="Leist S" first="Sarah R." last="Leist">Sarah R. Leist</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000000122483208</institution-id><institution-id institution-id-type="GRID">grid.10698.36</institution-id><institution>Department of Epidemiology,</institution><institution>University of North Carolina at Chapel Hill,</institution></institution-wrap>Chapel Hill, NC USA</nlm:aff><country>États-Unis</country><placeName><region type="state">Caroline du Nord</region></placeName><wicri:cityArea>Chapel Hill</wicri:cityArea></affiliation></author><author><name sortKey="Sch Fer, Alexandra" sort="Sch Fer, Alexandra" uniqKey="Sch Fer A" first="Alexandra" last="Sch Fer">Alexandra Sch Fer</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000000122483208</institution-id><institution-id institution-id-type="GRID">grid.10698.36</institution-id><institution>Department of Epidemiology,</institution><institution>University of North Carolina at Chapel Hill,</institution></institution-wrap>Chapel Hill, NC USA</nlm:aff><country>États-Unis</country><placeName><region type="state">Caroline du Nord</region></placeName><wicri:cityArea>Chapel Hill</wicri:cityArea></affiliation></author><author><name sortKey="Won, John" sort="Won, John" uniqKey="Won J" first="John" last="Won">John Won</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000000122483208</institution-id><institution-id institution-id-type="GRID">grid.10698.36</institution-id><institution>Department of Epidemiology,</institution><institution>University of North Carolina at Chapel Hill,</institution></institution-wrap>Chapel Hill, NC USA</nlm:aff><country>États-Unis</country><placeName><region type="state">Caroline du Nord</region></placeName><wicri:cityArea>Chapel Hill</wicri:cityArea></affiliation></author><author><name sortKey="Brown, Ariane J" sort="Brown, Ariane J" uniqKey="Brown A" first="Ariane J." last="Brown">Ariane J. 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Feng</name><affiliation wicri:level="2"><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0402 1634</institution-id><institution-id institution-id-type="GRID">grid.418227.a</institution-id><institution>Gilead Sciences, Inc,</institution></institution-wrap>Foster City, CA USA</nlm:aff><country>États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Foster City</wicri:cityArea></affiliation></author><author><name sortKey="Cihlar, Tomas" sort="Cihlar, Tomas" uniqKey="Cihlar T" first="Tomas" last="Cihlar">Tomas Cihlar</name><affiliation wicri:level="2"><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0402 1634</institution-id><institution-id institution-id-type="GRID">grid.418227.a</institution-id><institution>Gilead Sciences, Inc,</institution></institution-wrap>Foster City, CA USA</nlm:aff><country>États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Foster City</wicri:cityArea></affiliation></author><author><name sortKey="Jordan, Robert" sort="Jordan, Robert" uniqKey="Jordan R" first="Robert" last="Jordan">Robert Jordan</name><affiliation wicri:level="2"><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0402 1634</institution-id><institution-id institution-id-type="GRID">grid.418227.a</institution-id><institution>Gilead Sciences, Inc,</institution></institution-wrap>Foster City, CA USA</nlm:aff><country>États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Foster City</wicri:cityArea></affiliation></author><author><name sortKey="Denison, Mark R" sort="Denison, Mark R" uniqKey="Denison M" first="Mark R." last="Denison">Mark R. Denison</name><affiliation wicri:level="2"><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9916</institution-id><institution-id institution-id-type="GRID">grid.412807.8</institution-id><institution>Department of Pediatrics-Infectious Diseases, Department of Pathology, Microbiology and Immunology,</institution><institution>Vanderbilt University Medical Center,</institution></institution-wrap>Nashville, TN USA</nlm:aff><country>États-Unis</country><placeName><region type="state">Tennessee</region></placeName><wicri:cityArea>Nashville</wicri:cityArea></affiliation></author><author><name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S." last="Baric">Ralph S. Baric</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000000122483208</institution-id><institution-id institution-id-type="GRID">grid.10698.36</institution-id><institution>Department of Epidemiology,</institution><institution>University of North Carolina at Chapel Hill,</institution></institution-wrap>Chapel Hill, NC USA</nlm:aff><country>États-Unis</country><placeName><region type="state">Caroline du Nord</region></placeName><wicri:cityArea>Chapel Hill</wicri:cityArea></affiliation></author></analytic><series><title level="j">Nature Communications</title><idno type="eISSN">2041-1723</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 id="Par1">Middle East respiratory syndrome coronavirus (MERS-CoV) is the causative agent of a severe respiratory disease associated with more than 2468 human infections and over 851 deaths in 27 countries since 2012. There are no approved treatments for MERS-CoV infection although a combination of lopinavir, ritonavir and interferon beta (LPV/RTV-IFNb) is currently being evaluated in humans in the Kingdom of Saudi Arabia. Here, we show that remdesivir (RDV) and IFNb have superior antiviral activity to LPV and RTV in vitro. In mice, both prophylactic and therapeutic RDV improve pulmonary function and reduce lung viral loads and severe lung pathology. In contrast, prophylactic LPV/RTV-IFNb slightly reduces viral loads without impacting other disease parameters. Therapeutic LPV/RTV-IFNb improves pulmonary function but does not reduce virus replication or severe lung pathology. Thus, we provide in vivo evidence of the potential for RDV to treat MERS-CoV infections.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="De Wit, E" uniqKey="De Wit E">E de Wit</name></author><author><name sortKey="Van Doremalen, N" uniqKey="Van Doremalen N">N van Doremalen</name></author><author><name sortKey="Falzarano, D" uniqKey="Falzarano D">D Falzarano</name></author><author><name sortKey="Munster, Vj" uniqKey="Munster V">VJ Munster</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Muller, Ma" uniqKey="Muller M">MA Muller</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Morra, Me" uniqKey="Morra M">ME Morra</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Cho, Sy" uniqKey="Cho S">SY Cho</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Chan, Jf" uniqKey="Chan J">JF Chan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="De Wilde, Ah" uniqKey="De Wilde A">AH de Wilde</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hart, Bj" uniqKey="Hart B">BJ Hart</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chan, Jf" uniqKey="Chan J">JF Chan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kim, Uj" uniqKey="Kim U">UJ Kim</name></author><author><name sortKey="Won, Ej" uniqKey="Won E">EJ Won</name></author><author><name sortKey="Kee, Sj" uniqKey="Kee S">SJ Kee</name></author><author><name sortKey="Jung, Si" uniqKey="Jung S">SI Jung</name></author><author><name sortKey="Jang, Hc" uniqKey="Jang H">HC Jang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Spanakis, N" uniqKey="Spanakis N">N Spanakis</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Arabi, Ym" uniqKey="Arabi Y">YM Arabi</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Lo, Mk" uniqKey="Lo M">MK Lo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sheahan, Timothy P" uniqKey="Sheahan T">Timothy P. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Nat Commun</journal-id><journal-id journal-id-type="iso-abbrev">Nat Commun</journal-id><journal-title-group><journal-title>Nature Communications</journal-title></journal-title-group><issn pub-type="epub">2041-1723</issn><publisher><publisher-name>Nature Publishing Group UK</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31924756</article-id><article-id pub-id-type="pmc">6954302</article-id><article-id pub-id-type="publisher-id">13940</article-id><article-id pub-id-type="doi">10.1038/s41467-019-13940-6</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes" equal-contrib="yes"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0001-9181-2183</contrib-id><name><surname>Sheahan</surname><given-names>Timothy P.</given-names></name><address><email>sheahan@email.unc.edu</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Sims</surname><given-names>Amy C.</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Leist</surname><given-names>Sarah R.</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Schäfer</surname><given-names>Alexandra</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Won</surname><given-names>John</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Brown</surname><given-names>Ariane J.</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0001-8012-5302</contrib-id><name><surname>Montgomery</surname><given-names>Stephanie A.</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Hogg</surname><given-names>Alison</given-names></name><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0001-5599-1671</contrib-id><name><surname>Babusis</surname><given-names>Darius</given-names></name><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Clarke</surname><given-names>Michael O.</given-names></name><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Spahn</surname><given-names>Jamie E.</given-names></name><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Bauer</surname><given-names>Laura</given-names></name><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Sellers</surname><given-names>Scott</given-names></name><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Porter</surname><given-names>Danielle</given-names></name><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Feng</surname><given-names>Joy Y.</given-names></name><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Cihlar</surname><given-names>Tomas</given-names></name><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Jordan</surname><given-names>Robert</given-names></name><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0003-2655-0900</contrib-id><name><surname>Denison</surname><given-names>Mark R.</given-names></name><xref ref-type="aff" rid="Aff4">4</xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Baric</surname><given-names>Ralph S.</given-names></name><address><email>rbaric@email.unc.edu</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><aff id="Aff1"><label>1</label><institution-wrap><institution-id institution-id-type="ISNI">0000000122483208</institution-id><institution-id institution-id-type="GRID">grid.10698.36</institution-id><institution>Department of Epidemiology,</institution><institution>University of North Carolina at Chapel Hill,</institution></institution-wrap>Chapel Hill, NC USA</aff><aff id="Aff2"><label>2</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 1034 1720</institution-id><institution-id institution-id-type="GRID">grid.410711.2</institution-id><institution>Department of Pathology & Laboratory Medicine,</institution><institution>University of North Carolina,</institution></institution-wrap>Chapel Hill, NC USA</aff><aff id="Aff3"><label>3</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0402 1634</institution-id><institution-id institution-id-type="GRID">grid.418227.a</institution-id><institution>Gilead Sciences, Inc,</institution></institution-wrap>Foster City, CA USA</aff><aff id="Aff4"><label>4</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9916</institution-id><institution-id institution-id-type="GRID">grid.412807.8</institution-id><institution>Department of Pediatrics-Infectious Diseases, Department of Pathology, Microbiology and Immunology,</institution><institution>Vanderbilt University Medical Center,</institution></institution-wrap>Nashville, TN USA</aff></contrib-group><pub-date pub-type="epub"><day>10</day><month>1</month><year>2020</year></pub-date><pub-date pub-type="pmc-release"><day>10</day><month>1</month><year>2020</year></pub-date><pub-date pub-type="collection"><year>2020</year></pub-date><volume>11</volume><elocation-id>222</elocation-id><history><date date-type="received"><day>3</day><month>1</month><year>2019</year></date><date date-type="accepted"><day>7</day><month>12</month><year>2019</year></date></history><permissions><copyright-statement>© The Author(s) 2020</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold> This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>.</license-p></license></permissions><abstract id="Abs1"><p id="Par1">Middle East respiratory syndrome coronavirus (MERS-CoV) is the causative agent of a severe respiratory disease associated with more than 2468 human infections and over 851 deaths in 27 countries since 2012. There are no approved treatments for MERS-CoV infection although a combination of lopinavir, ritonavir and interferon beta (LPV/RTV-IFNb) is currently being evaluated in humans in the Kingdom of Saudi Arabia. Here, we show that remdesivir (RDV) and IFNb have superior antiviral activity to LPV and RTV in vitro. In mice, both prophylactic and therapeutic RDV improve pulmonary function and reduce lung viral loads and severe lung pathology. In contrast, prophylactic LPV/RTV-IFNb slightly reduces viral loads without impacting other disease parameters. Therapeutic LPV/RTV-IFNb improves pulmonary function but does not reduce virus replication or severe lung pathology. Thus, we provide in vivo evidence of the potential for RDV to treat MERS-CoV infections.</p></abstract><abstract id="Abs2" abstract-type="web-summary"><p id="Par2">Remdesivir (RDV) is a broad-spectrum antiviral drug with activity against MERS coronavirus, but in vivo efficacy has not been evaluated. Here, the authors show that RDV has superior anti-MERS activity in vitro and in vivo compared to combination therapy with lopinavir, ritonavir and interferon beta and reduces severe lung pathology.</p></abstract><kwd-group kwd-group-type="npg-subject"><title>Subject terms</title><kwd>Antiviral agents</kwd><kwd>Viral pathogenesis</kwd><kwd>Viral infection</kwd><kwd>Drug development</kwd></kwd-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/100000060</institution-id><institution>U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)</institution></institution-wrap></funding-source><award-id>5R01AI132178</award-id><principal-award-recipient><name><surname>Sheahan</surname><given-names>Timothy P.</given-names></name></principal-award-recipient></award-group></funding-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/100005564</institution-id><institution>Gilead Sciences (Gilead)</institution></institution-wrap></funding-source></award-group></funding-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2020</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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