An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice.
Identifieur interne : 000299 ( Main/Exploration ); précédent : 000298; suivant : 000300An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice.
Auteurs : Timothy P. Sheahan [États-Unis] ; Amy C. Sims [États-Unis] ; Shuntai Zhou [États-Unis] ; Rachel L. Graham [États-Unis] ; Andrea J. Pruijssers [États-Unis] ; Maria L. Agostini [États-Unis] ; Sarah R. Leist [États-Unis] ; Alexandra Sch Fer [États-Unis] ; Kenneth H. Dinnon [États-Unis] ; Laura J. Stevens [États-Unis] ; James D. Chappell [États-Unis] ; Xiaotao Lu [États-Unis] ; Tia M. Hughes [États-Unis] ; Amelia S. George [États-Unis] ; Collin S. Hill [États-Unis] ; Stephanie A. Montgomery [États-Unis] ; Ariane J. Brown [États-Unis] ; Gregory R. Bluemling [États-Unis] ; Michael G. Natchus [États-Unis] ; Manohar Saindane [États-Unis] ; Alexander A. Kolykhalov [États-Unis] ; George Painter [États-Unis] ; Jennifer Harcourt ; Azaibi Tamin ; Natalie J. Thornburg ; Ronald Swanstrom [États-Unis] ; Mark R. Denison [États-Unis] ; Ralph S. Baric [États-Unis]Source :
- Science translational medicine [ 1946-6242 ] ; 2020.
Abstract
Coronaviruses (CoVs) traffic frequently between species resulting in novel disease outbreaks, most recently exemplified by the newly emerged SARS-CoV-2, the causative agent of COVID-19. Herein, we show that the ribonucleoside analog β-D-N4-hydroxycytidine (NHC, EIDD-1931) has broad spectrum antiviral activity against SARS-CoV-2, MERS-CoV, SARS-CoV, and related zoonotic group 2b or 2c Bat-CoVs, as well as increased potency against a coronavirus bearing resistance mutations to the nucleoside analog inhibitor remdesivir. In mice infected with SARS-CoV or MERS-CoV, both prophylactic and therapeutic administration of EIDD-2801, an orally bioavailable NHC-prodrug (β-D-N4-hydroxycytidine-5'-isopropyl ester), improved pulmonary function, and reduced virus titer and body weight loss. Decreased MERS-CoV yields in vitro and in vivo were associated with increased transition mutation frequency in viral but not host cell RNA, supporting a mechanism of lethal mutagenesis in CoV. The potency of NHC/EIDD-2801 against multiple coronaviruses and oral bioavailability highlight its potential utility as an effective antiviral against SARS-CoV-2 and other future zoonotic coronaviruses.
DOI: 10.1126/scitranslmed.abb5883
PubMed: 32253226
Affiliations:
- États-Unis
- Caroline du Nord
- Chapel Hill (Caroline du Nord)
- Université de Caroline du Nord à Chapel Hill
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Le document en format XML
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Sheahan</name><affiliation wicri:level="4"><nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. sheahan@email.unc.edu rbaric@email.unc.edu.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599</wicri:regionArea><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName><placeName><settlement type="city">Chapel Hill (Caroline du Nord)</settlement><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Sims, Amy C" sort="Sims, Amy C" uniqKey="Sims A" first="Amy C" last="Sims">Amy C. 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Dinnon</name><affiliation wicri:level="4"><nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599</wicri:regionArea><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName><placeName><settlement type="city">Chapel Hill (Caroline du Nord)</settlement><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Stevens, Laura J" sort="Stevens, Laura J" uniqKey="Stevens L" first="Laura J" last="Stevens">Laura J. 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Chappell</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, TN, 37232,USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, TN, 37232</wicri:regionArea><wicri:noRegion>37232</wicri:noRegion></affiliation></author><author><name sortKey="Lu, Xiaotao" sort="Lu, Xiaotao" uniqKey="Lu X" first="Xiaotao" last="Lu">Xiaotao Lu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, TN, 37232,USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, TN, 37232</wicri:regionArea><wicri:noRegion>37232</wicri:noRegion></affiliation></author><author><name sortKey="Hughes, Tia M" sort="Hughes, Tia M" uniqKey="Hughes T" first="Tia M" last="Hughes">Tia M. Hughes</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, TN, 37232,USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, TN, 37232</wicri:regionArea><wicri:noRegion>37232</wicri:noRegion></affiliation></author><author><name sortKey="George, Amelia S" sort="George, Amelia S" uniqKey="George A" first="Amelia S" last="George">Amelia S. 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Montgomery</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC, 27599</wicri:regionArea><wicri:noRegion>27599</wicri:noRegion></affiliation></author><author><name sortKey="Brown, Ariane J" sort="Brown, Ariane J" uniqKey="Brown A" first="Ariane J" last="Brown">Ariane J. Brown</name><affiliation wicri:level="4"><nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599</wicri:regionArea><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName><placeName><settlement type="city">Chapel Hill (Caroline du Nord)</settlement><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Bluemling, Gregory R" sort="Bluemling, Gregory R" uniqKey="Bluemling G" first="Gregory R" last="Bluemling">Gregory R. Bluemling</name><affiliation wicri:level="1"><nlm:affiliation>Emory Institute of Drug Development (EIDD), Emory University, Atlanta, GA, 30322, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Emory Institute of Drug Development (EIDD), Emory University, Atlanta, GA, 30322</wicri:regionArea><wicri:noRegion>30322</wicri:noRegion></affiliation></author><author><name sortKey="Natchus, Michael G" sort="Natchus, Michael G" uniqKey="Natchus M" first="Michael G" last="Natchus">Michael G. Natchus</name><affiliation wicri:level="1"><nlm:affiliation>Emory Institute of Drug Development (EIDD), Emory University, Atlanta, GA, 30322, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Emory Institute of Drug Development (EIDD), Emory University, Atlanta, GA, 30322</wicri:regionArea><wicri:noRegion>30322</wicri:noRegion></affiliation></author><author><name sortKey="Saindane, Manohar" sort="Saindane, Manohar" uniqKey="Saindane M" first="Manohar" last="Saindane">Manohar Saindane</name><affiliation wicri:level="1"><nlm:affiliation>Emory Institute of Drug Development (EIDD), Emory University, Atlanta, GA, 30322, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Emory Institute of Drug Development (EIDD), Emory University, Atlanta, GA, 30322</wicri:regionArea><wicri:noRegion>30322</wicri:noRegion></affiliation></author><author><name sortKey="Kolykhalov, Alexander A" sort="Kolykhalov, Alexander A" uniqKey="Kolykhalov A" first="Alexander A" last="Kolykhalov">Alexander A. Kolykhalov</name><affiliation wicri:level="1"><nlm:affiliation>Emory Institute of Drug Development (EIDD), Emory University, Atlanta, GA, 30322, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Emory Institute of Drug Development (EIDD), Emory University, Atlanta, GA, 30322</wicri:regionArea><wicri:noRegion>30322</wicri:noRegion></affiliation></author><author><name sortKey="Painter, George" sort="Painter, George" uniqKey="Painter G" first="George" last="Painter">George Painter</name><affiliation wicri:level="1"><nlm:affiliation>Emory Institute of Drug Development (EIDD), Emory University, Atlanta, GA, 30322, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Emory Institute of Drug Development (EIDD), Emory University, Atlanta, GA, 30322</wicri:regionArea><wicri:noRegion>30322</wicri:noRegion></affiliation></author><author><name sortKey="Harcourt, Jennifer" sort="Harcourt, Jennifer" uniqKey="Harcourt J" first="Jennifer" last="Harcourt">Jennifer Harcourt</name><affiliation><nlm:affiliation>Centers for Disease Control and Prevention, Division of Viral Diseases Atlanta GA.</nlm:affiliation><wicri:noCountry code="subField">Division of Viral Diseases Atlanta GA</wicri:noCountry></affiliation></author><author><name sortKey="Tamin, Azaibi" sort="Tamin, Azaibi" uniqKey="Tamin A" first="Azaibi" last="Tamin">Azaibi Tamin</name><affiliation><nlm:affiliation>Centers for Disease Control and Prevention, Division of Viral Diseases Atlanta GA.</nlm:affiliation><wicri:noCountry code="subField">Division of Viral Diseases Atlanta GA</wicri:noCountry></affiliation></author><author><name sortKey="Thornburg, Natalie J" sort="Thornburg, Natalie J" uniqKey="Thornburg N" first="Natalie J" last="Thornburg">Natalie J. Thornburg</name><affiliation><nlm:affiliation>Centers for Disease Control and Prevention, Division of Viral Diseases Atlanta GA.</nlm:affiliation><wicri:noCountry code="subField">Division of Viral Diseases Atlanta GA</wicri:noCountry></affiliation></author><author><name sortKey="Swanstrom, Ronald" sort="Swanstrom, Ronald" uniqKey="Swanstrom R" first="Ronald" last="Swanstrom">Ronald Swanstrom</name><affiliation wicri:level="4"><nlm:affiliation>Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599</wicri:regionArea><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName><placeName><settlement type="city">Chapel Hill (Caroline du Nord)</settlement><region type="state">Caroline du Nord</region></placeName></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="1"><nlm:affiliation>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, TN, 37232,USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, TN, 37232</wicri:regionArea><wicri:noRegion>37232</wicri:noRegion></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="4"><nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. sheahan@email.unc.edu rbaric@email.unc.edu.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599</wicri:regionArea><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName><placeName><settlement type="city">Chapel Hill (Caroline du Nord)</settlement><region type="state">Caroline du Nord</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2020">2020</date><idno type="RBID">pubmed:32253226</idno><idno type="pmid">32253226</idno><idno type="doi">10.1126/scitranslmed.abb5883</idno><idno type="wicri:Area/PubMed/Corpus">000079</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000079</idno><idno type="wicri:Area/PubMed/Curation">000079</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000079</idno><idno type="wicri:Area/PubMed/Checkpoint">000305</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000305</idno><idno type="wicri:Area/Ncbi/Merge">002710</idno><idno type="wicri:Area/Ncbi/Curation">002710</idno><idno type="wicri:Area/Ncbi/Checkpoint">002710</idno><idno type="wicri:Area/Main/Merge">000302</idno><idno type="wicri:Area/Main/Curation">000299</idno><idno type="wicri:Area/Main/Exploration">000299</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice.</title><author><name sortKey="Sheahan, Timothy P" sort="Sheahan, Timothy P" uniqKey="Sheahan T" first="Timothy P" last="Sheahan">Timothy P. Sheahan</name><affiliation wicri:level="4"><nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. sheahan@email.unc.edu rbaric@email.unc.edu.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599</wicri:regionArea><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName><placeName><settlement type="city">Chapel Hill (Caroline du Nord)</settlement><region type="state">Caroline du Nord</region></placeName></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="4"><nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599</wicri:regionArea><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName><placeName><settlement type="city">Chapel Hill (Caroline du Nord)</settlement><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Zhou, Shuntai" sort="Zhou, Shuntai" uniqKey="Zhou S" first="Shuntai" last="Zhou">Shuntai Zhou</name><affiliation wicri:level="4"><nlm:affiliation>Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599</wicri:regionArea><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName><placeName><settlement type="city">Chapel Hill (Caroline du Nord)</settlement><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Graham, Rachel L" sort="Graham, Rachel L" uniqKey="Graham R" first="Rachel L" last="Graham">Rachel L. Graham</name><affiliation wicri:level="4"><nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599</wicri:regionArea><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName><placeName><settlement type="city">Chapel Hill (Caroline du Nord)</settlement><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Pruijssers, Andrea J" sort="Pruijssers, Andrea J" uniqKey="Pruijssers A" first="Andrea J" last="Pruijssers">Andrea J. Pruijssers</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, TN, 37232,USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, TN, 37232</wicri:regionArea><wicri:noRegion>37232</wicri:noRegion></affiliation></author><author><name sortKey="Agostini, Maria L" sort="Agostini, Maria L" uniqKey="Agostini M" first="Maria L" last="Agostini">Maria L. Agostini</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, TN, 37232,USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, TN, 37232</wicri:regionArea><wicri:noRegion>37232</wicri:noRegion></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="4"><nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599</wicri:regionArea><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName><placeName><settlement type="city">Chapel Hill (Caroline du Nord)</settlement><region type="state">Caroline du Nord</region></placeName></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="4"><nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599</wicri:regionArea><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName><placeName><settlement type="city">Chapel Hill (Caroline du Nord)</settlement><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Dinnon, Kenneth H" sort="Dinnon, Kenneth H" uniqKey="Dinnon K" first="Kenneth H" last="Dinnon">Kenneth H. Dinnon</name><affiliation wicri:level="4"><nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599</wicri:regionArea><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName><placeName><settlement type="city">Chapel Hill (Caroline du Nord)</settlement><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Stevens, Laura J" sort="Stevens, Laura J" uniqKey="Stevens L" first="Laura J" last="Stevens">Laura J. Stevens</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, TN, 37232,USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, TN, 37232</wicri:regionArea><wicri:noRegion>37232</wicri:noRegion></affiliation></author><author><name sortKey="Chappell, James D" sort="Chappell, James D" uniqKey="Chappell J" first="James D" last="Chappell">James D. Chappell</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, TN, 37232,USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, TN, 37232</wicri:regionArea><wicri:noRegion>37232</wicri:noRegion></affiliation></author><author><name sortKey="Lu, Xiaotao" sort="Lu, Xiaotao" uniqKey="Lu X" first="Xiaotao" last="Lu">Xiaotao Lu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, TN, 37232,USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, TN, 37232</wicri:regionArea><wicri:noRegion>37232</wicri:noRegion></affiliation></author><author><name sortKey="Hughes, Tia M" sort="Hughes, Tia M" uniqKey="Hughes T" first="Tia M" last="Hughes">Tia M. Hughes</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, TN, 37232,USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, TN, 37232</wicri:regionArea><wicri:noRegion>37232</wicri:noRegion></affiliation></author><author><name sortKey="George, Amelia S" sort="George, Amelia S" uniqKey="George A" first="Amelia S" last="George">Amelia S. George</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, TN, 37232,USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, TN, 37232</wicri:regionArea><wicri:noRegion>37232</wicri:noRegion></affiliation></author><author><name sortKey="Hill, Collin S" sort="Hill, Collin S" uniqKey="Hill C" first="Collin S" last="Hill">Collin S. Hill</name><affiliation wicri:level="4"><nlm:affiliation>Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599</wicri:regionArea><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName><placeName><settlement type="city">Chapel Hill (Caroline du Nord)</settlement><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Montgomery, Stephanie A" sort="Montgomery, Stephanie A" uniqKey="Montgomery S" first="Stephanie A" last="Montgomery">Stephanie A. Montgomery</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC, 27599</wicri:regionArea><wicri:noRegion>27599</wicri:noRegion></affiliation></author><author><name sortKey="Brown, Ariane J" sort="Brown, Ariane J" uniqKey="Brown A" first="Ariane J" last="Brown">Ariane J. Brown</name><affiliation wicri:level="4"><nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599</wicri:regionArea><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName><placeName><settlement type="city">Chapel Hill (Caroline du Nord)</settlement><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Bluemling, Gregory R" sort="Bluemling, Gregory R" uniqKey="Bluemling G" first="Gregory R" last="Bluemling">Gregory R. Bluemling</name><affiliation wicri:level="1"><nlm:affiliation>Emory Institute of Drug Development (EIDD), Emory University, Atlanta, GA, 30322, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Emory Institute of Drug Development (EIDD), Emory University, Atlanta, GA, 30322</wicri:regionArea><wicri:noRegion>30322</wicri:noRegion></affiliation></author><author><name sortKey="Natchus, Michael G" sort="Natchus, Michael G" uniqKey="Natchus M" first="Michael G" last="Natchus">Michael G. Natchus</name><affiliation wicri:level="1"><nlm:affiliation>Emory Institute of Drug Development (EIDD), Emory University, Atlanta, GA, 30322, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Emory Institute of Drug Development (EIDD), Emory University, Atlanta, GA, 30322</wicri:regionArea><wicri:noRegion>30322</wicri:noRegion></affiliation></author><author><name sortKey="Saindane, Manohar" sort="Saindane, Manohar" uniqKey="Saindane M" first="Manohar" last="Saindane">Manohar Saindane</name><affiliation wicri:level="1"><nlm:affiliation>Emory Institute of Drug Development (EIDD), Emory University, Atlanta, GA, 30322, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Emory Institute of Drug Development (EIDD), Emory University, Atlanta, GA, 30322</wicri:regionArea><wicri:noRegion>30322</wicri:noRegion></affiliation></author><author><name sortKey="Kolykhalov, Alexander A" sort="Kolykhalov, Alexander A" uniqKey="Kolykhalov A" first="Alexander A" last="Kolykhalov">Alexander A. Kolykhalov</name><affiliation wicri:level="1"><nlm:affiliation>Emory Institute of Drug Development (EIDD), Emory University, Atlanta, GA, 30322, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Emory Institute of Drug Development (EIDD), Emory University, Atlanta, GA, 30322</wicri:regionArea><wicri:noRegion>30322</wicri:noRegion></affiliation></author><author><name sortKey="Painter, George" sort="Painter, George" uniqKey="Painter G" first="George" last="Painter">George Painter</name><affiliation wicri:level="1"><nlm:affiliation>Emory Institute of Drug Development (EIDD), Emory University, Atlanta, GA, 30322, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Emory Institute of Drug Development (EIDD), Emory University, Atlanta, GA, 30322</wicri:regionArea><wicri:noRegion>30322</wicri:noRegion></affiliation></author><author><name sortKey="Harcourt, Jennifer" sort="Harcourt, Jennifer" uniqKey="Harcourt J" first="Jennifer" last="Harcourt">Jennifer Harcourt</name><affiliation><nlm:affiliation>Centers for Disease Control and Prevention, Division of Viral Diseases Atlanta GA.</nlm:affiliation><wicri:noCountry code="subField">Division of Viral Diseases Atlanta GA</wicri:noCountry></affiliation></author><author><name sortKey="Tamin, Azaibi" sort="Tamin, Azaibi" uniqKey="Tamin A" first="Azaibi" last="Tamin">Azaibi Tamin</name><affiliation><nlm:affiliation>Centers for Disease Control and Prevention, Division of Viral Diseases Atlanta GA.</nlm:affiliation><wicri:noCountry code="subField">Division of Viral Diseases Atlanta GA</wicri:noCountry></affiliation></author><author><name sortKey="Thornburg, Natalie J" sort="Thornburg, Natalie J" uniqKey="Thornburg N" first="Natalie J" last="Thornburg">Natalie J. Thornburg</name><affiliation><nlm:affiliation>Centers for Disease Control and Prevention, Division of Viral Diseases Atlanta GA.</nlm:affiliation><wicri:noCountry code="subField">Division of Viral Diseases Atlanta GA</wicri:noCountry></affiliation></author><author><name sortKey="Swanstrom, Ronald" sort="Swanstrom, Ronald" uniqKey="Swanstrom R" first="Ronald" last="Swanstrom">Ronald Swanstrom</name><affiliation wicri:level="4"><nlm:affiliation>Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599</wicri:regionArea><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName><placeName><settlement type="city">Chapel Hill (Caroline du Nord)</settlement><region type="state">Caroline du Nord</region></placeName></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="1"><nlm:affiliation>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, TN, 37232,USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, TN, 37232</wicri:regionArea><wicri:noRegion>37232</wicri:noRegion></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="4"><nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. sheahan@email.unc.edu rbaric@email.unc.edu.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599</wicri:regionArea><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName><placeName><settlement type="city">Chapel Hill (Caroline du Nord)</settlement><region type="state">Caroline du Nord</region></placeName></affiliation></author></analytic><series><title level="j">Science translational medicine</title><idno type="eISSN">1946-6242</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">Coronaviruses (CoVs) traffic frequently between species resulting in novel disease outbreaks, most recently exemplified by the newly emerged SARS-CoV-2, the causative agent of COVID-19. Herein, we show that the ribonucleoside analog β-D-N<sup>4</sup>-hydroxycytidine (NHC, EIDD-1931) has broad spectrum antiviral activity against SARS-CoV-2, MERS-CoV, SARS-CoV, and related zoonotic group 2b or 2c Bat-CoVs, as well as increased potency against a coronavirus bearing resistance mutations to the nucleoside analog inhibitor remdesivir. In mice infected with SARS-CoV or MERS-CoV, both prophylactic and therapeutic administration of EIDD-2801, an orally bioavailable NHC-prodrug (β-D-N<sup>4</sup>-hydroxycytidine-5'-isopropyl ester), improved pulmonary function, and reduced virus titer and body weight loss. Decreased MERS-CoV yields in vitro and in vivo were associated with increased transition mutation frequency in viral but not host cell RNA, supporting a mechanism of lethal mutagenesis in CoV. The potency of NHC/EIDD-2801 against multiple coronaviruses and oral bioavailability highlight its potential utility as an effective antiviral against SARS-CoV-2 and other future zoonotic coronaviruses.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Caroline du Nord</li></region><settlement><li>Chapel Hill (Caroline du Nord)</li></settlement><orgName><li>Université de Caroline du Nord à Chapel Hill</li></orgName></list><tree><noCountry><name sortKey="Harcourt, Jennifer" sort="Harcourt, Jennifer" uniqKey="Harcourt J" first="Jennifer" last="Harcourt">Jennifer Harcourt</name><name sortKey="Tamin, Azaibi" sort="Tamin, Azaibi" uniqKey="Tamin A" first="Azaibi" last="Tamin">Azaibi Tamin</name><name sortKey="Thornburg, Natalie J" sort="Thornburg, Natalie J" uniqKey="Thornburg N" first="Natalie J" last="Thornburg">Natalie J. Thornburg</name></noCountry><country name="États-Unis"><region name="Caroline du Nord"><name sortKey="Sheahan, Timothy P" sort="Sheahan, Timothy P" uniqKey="Sheahan T" first="Timothy P" last="Sheahan">Timothy P. Sheahan</name></region><name sortKey="Agostini, Maria L" sort="Agostini, Maria L" uniqKey="Agostini M" first="Maria L" last="Agostini">Maria L. Agostini</name><name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S" last="Baric">Ralph S. Baric</name><name sortKey="Bluemling, Gregory R" sort="Bluemling, Gregory R" uniqKey="Bluemling G" first="Gregory R" last="Bluemling">Gregory R. Bluemling</name><name sortKey="Brown, Ariane J" sort="Brown, Ariane J" uniqKey="Brown A" first="Ariane J" last="Brown">Ariane J. Brown</name><name sortKey="Chappell, James D" sort="Chappell, James D" uniqKey="Chappell J" first="James D" last="Chappell">James D. Chappell</name><name sortKey="Denison, Mark R" sort="Denison, Mark R" uniqKey="Denison M" first="Mark R" last="Denison">Mark R. Denison</name><name sortKey="Dinnon, Kenneth H" sort="Dinnon, Kenneth H" uniqKey="Dinnon K" first="Kenneth H" last="Dinnon">Kenneth H. Dinnon</name><name sortKey="George, Amelia S" sort="George, Amelia S" uniqKey="George A" first="Amelia S" last="George">Amelia S. George</name><name sortKey="Graham, Rachel L" sort="Graham, Rachel L" uniqKey="Graham R" first="Rachel L" last="Graham">Rachel L. Graham</name><name sortKey="Hill, Collin S" sort="Hill, Collin S" uniqKey="Hill C" first="Collin S" last="Hill">Collin S. Hill</name><name sortKey="Hughes, Tia M" sort="Hughes, Tia M" uniqKey="Hughes T" first="Tia M" last="Hughes">Tia M. Hughes</name><name sortKey="Kolykhalov, Alexander A" sort="Kolykhalov, Alexander A" uniqKey="Kolykhalov A" first="Alexander A" last="Kolykhalov">Alexander A. Kolykhalov</name><name sortKey="Leist, Sarah R" sort="Leist, Sarah R" uniqKey="Leist S" first="Sarah R" last="Leist">Sarah R. Leist</name><name sortKey="Lu, Xiaotao" sort="Lu, Xiaotao" uniqKey="Lu X" first="Xiaotao" last="Lu">Xiaotao Lu</name><name sortKey="Montgomery, Stephanie A" sort="Montgomery, Stephanie A" uniqKey="Montgomery S" first="Stephanie A" last="Montgomery">Stephanie A. Montgomery</name><name sortKey="Natchus, Michael G" sort="Natchus, Michael G" uniqKey="Natchus M" first="Michael G" last="Natchus">Michael G. Natchus</name><name sortKey="Painter, George" sort="Painter, George" uniqKey="Painter G" first="George" last="Painter">George Painter</name><name sortKey="Pruijssers, Andrea J" sort="Pruijssers, Andrea J" uniqKey="Pruijssers A" first="Andrea J" last="Pruijssers">Andrea J. Pruijssers</name><name sortKey="Saindane, Manohar" sort="Saindane, Manohar" uniqKey="Saindane M" first="Manohar" last="Saindane">Manohar Saindane</name><name sortKey="Sch Fer, Alexandra" sort="Sch Fer, Alexandra" uniqKey="Sch Fer A" first="Alexandra" last="Sch Fer">Alexandra Sch Fer</name><name sortKey="Sims, Amy C" sort="Sims, Amy C" uniqKey="Sims A" first="Amy C" last="Sims">Amy C. Sims</name><name sortKey="Stevens, Laura J" sort="Stevens, Laura J" uniqKey="Stevens L" first="Laura J" last="Stevens">Laura J. Stevens</name><name sortKey="Swanstrom, Ronald" sort="Swanstrom, Ronald" uniqKey="Swanstrom R" first="Ronald" last="Swanstrom">Ronald Swanstrom</name><name sortKey="Zhou, Shuntai" sort="Zhou, Shuntai" uniqKey="Zhou S" first="Shuntai" last="Zhou">Shuntai Zhou</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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