MersV1, Main, Exploration, bibRecord, 000E75

Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses.

Identifieur interne : 000E75 ( Main/Exploration ); précédent : 000E74; suivant : 000E76

Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses.

Auteurs : Timothy P. Sheahan [États-Unis] ; Amy C. Sims [États-Unis] ; Rachel L. Graham [États-Unis] ; Vineet D. Menachery [États-Unis] ; Lisa E. Gralinski [États-Unis] ; James B. Case [États-Unis] ; Sarah R. Leist [États-Unis] ; Krzysztof Pyrc [Pologne] ; Joy Y. Feng [États-Unis] ; Iva Trantcheva [États-Unis] ; Roy Bannister [États-Unis] ; Yeojin Park [États-Unis] ; Darius Babusis [États-Unis] ; Michael O. Clarke [États-Unis] ; Richard L. Mackman [États-Unis] ; Jamie E. Spahn [États-Unis] ; Christopher A. Palmiotti [États-Unis] ; Dustin Siegel [États-Unis] ; Adrian S. Ray [États-Unis] ; Tomas Cihlar [États-Unis] ; Robert Jordan [États-Unis] ; Mark R. Denison [États-Unis] ; Ralph S. Baric [États-Unis]

Source :

Science translational medicine [ 1946-6242 ] ; 2017.

RBID : pubmed:28659436

Descripteurs français

KwdFr :
- Alanine (analogues et dérivés), Alanine (métabolisme), Alanine (pharmacocinétique), Alanine (pharmacologie), Alanine (toxicité), Animaux, Antiviraux (métabolisme), Antiviraux (pharmacocinétique), Antiviraux (pharmacologie), Antiviraux (toxicité), Callithrix, Cellules épithéliales (virologie), Coronavirus (), Humains, Lignée cellulaire, Poumon (anatomopathologie), Ribonucléotides (métabolisme), Ribonucléotides (pharmacocinétique), Ribonucléotides (pharmacologie), Ribonucléotides (toxicité), Réplication virale (), Souris, Zoonoses (), Zoonoses (virologie), Zoonoses (épidémiologie), Épidémies.
MESH :
- analogues et dérivés : Alanine.
- anatomopathologie : Poumon.
- métabolisme : Alanine, Antiviraux, Ribonucléotides.
- pharmacocinétique : Alanine, Antiviraux, Ribonucléotides.
- pharmacologie : Alanine, Antiviraux, Ribonucléotides.
- toxicité : Alanine, Antiviraux, Ribonucléotides.
- virologie : Cellules épithéliales, Zoonoses.
- épidémiologie : Zoonoses.
- Animaux, Callithrix, Coronavirus, Humains, Lignée cellulaire, Réplication virale, Souris, Zoonoses, Épidémies.

English descriptors

KwdEn :
- Alanine (analogs & derivatives), Alanine (metabolism), Alanine (pharmacokinetics), Alanine (pharmacology), Alanine (toxicity), Animals, Antiviral Agents (metabolism), Antiviral Agents (pharmacokinetics), Antiviral Agents (pharmacology), Antiviral Agents (toxicity), Callithrix, Cell Line, Coronavirus (drug effects), Epidemics, Epithelial Cells (virology), Humans, Lung (pathology), Mice, Ribonucleotides (metabolism), Ribonucleotides (pharmacokinetics), Ribonucleotides (pharmacology), Ribonucleotides (toxicity), Virus Replication (drug effects), Zoonoses (epidemiology), Zoonoses (prevention & control), Zoonoses (virology).
MESH :
- chemical , analogs & derivatives : Alanine.
- chemical , metabolism : Alanine, Antiviral Agents, Ribonucleotides.
- chemical , pharmacokinetics : Alanine, Antiviral Agents, Ribonucleotides.
- chemical , pharmacology : Alanine, Antiviral Agents, Ribonucleotides.
- chemical , toxicity : Alanine, Antiviral Agents, Ribonucleotides.
- drug effects : Coronavirus, Virus Replication.
- epidemiology : Zoonoses.
- pathology : Lung.
- prevention & control : Zoonoses.
- virology : Epithelial Cells, Zoonoses.
- Animals, Callithrix, Cell Line, Epidemics, Humans, Mice.

Abstract

Emerging viral infections are difficult to control because heterogeneous members periodically cycle in and out of humans and zoonotic hosts, complicating the development of specific antiviral therapies and vaccines. Coronaviruses (CoVs) have a proclivity to spread rapidly into new host species causing severe disease. Severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV) successively emerged, causing severe epidemic respiratory disease in immunologically naïve human populations throughout the globe. Broad-spectrum therapies capable of inhibiting CoV infections would address an immediate unmet medical need and could be invaluable in the treatment of emerging and endemic CoV infections. We show that a nucleotide prodrug, GS-5734, currently in clinical development for treatment of Ebola virus disease, can inhibit SARS-CoV and MERS-CoV replication in multiple in vitro systems, including primary human airway epithelial cell cultures with submicromolar IC₅₀ values. GS-5734 was also effective against bat CoVs, prepandemic bat CoVs, and circulating contemporary human CoV in primary human lung cells, thus demonstrating broad-spectrum anti-CoV activity. In a mouse model of SARS-CoV pathogenesis, prophylactic and early therapeutic administration of GS-5734 significantly reduced lung viral load and improved clinical signs of disease as well as respiratory function. These data provide substantive evidence that GS-5734 may prove effective against endemic MERS-CoV in the Middle East, circulating human CoV, and, possibly most importantly, emerging CoV of the future.

DOI: 10.1126/scitranslmed.aal3653
PubMed: 28659436

Affiliations:

Le document en format XML

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<author><name sortKey="Leist, Sarah R" sort="Leist, Sarah R" uniqKey="Leist S" first="Sarah R" last="Leist">Sarah R. Leist</name>
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<author><name sortKey="Pyrc, Krzysztof" sort="Pyrc, Krzysztof" uniqKey="Pyrc K" first="Krzysztof" last="Pyrc">Krzysztof Pyrc</name>
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<author><name sortKey="Feng, Joy Y" sort="Feng, Joy Y" uniqKey="Feng J" first="Joy Y" last="Feng">Joy Y. Feng</name>
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<author><name sortKey="Trantcheva, Iva" sort="Trantcheva, Iva" uniqKey="Trantcheva I" first="Iva" last="Trantcheva">Iva Trantcheva</name>
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<author><name sortKey="Bannister, Roy" sort="Bannister, Roy" uniqKey="Bannister R" first="Roy" last="Bannister">Roy Bannister</name>
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<author><name sortKey="Park, Yeojin" sort="Park, Yeojin" uniqKey="Park Y" first="Yeojin" last="Park">Yeojin Park</name>
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<author><name sortKey="Babusis, Darius" sort="Babusis, Darius" uniqKey="Babusis D" first="Darius" last="Babusis">Darius Babusis</name>
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</placeName>
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<author><name sortKey="Clarke, Michael O" sort="Clarke, Michael O" uniqKey="Clarke M" first="Michael O" last="Clarke">Michael O. Clarke</name>
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<author><name sortKey="Mackman, Richard L" sort="Mackman, Richard L" uniqKey="Mackman R" first="Richard L" last="Mackman">Richard L. Mackman</name>
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<author><name sortKey="Spahn, Jamie E" sort="Spahn, Jamie E" uniqKey="Spahn J" first="Jamie E" last="Spahn">Jamie E. Spahn</name>
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</placeName>
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<author><name sortKey="Palmiotti, Christopher A" sort="Palmiotti, Christopher A" uniqKey="Palmiotti C" first="Christopher A" last="Palmiotti">Christopher A. Palmiotti</name>
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<author><name sortKey="Siegel, Dustin" sort="Siegel, Dustin" uniqKey="Siegel D" first="Dustin" last="Siegel">Dustin Siegel</name>
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<author><name sortKey="Ray, Adrian S" sort="Ray, Adrian S" uniqKey="Ray A" first="Adrian S" last="Ray">Adrian S. Ray</name>
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<country xml:lang="fr">États-Unis</country>
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</placeName>
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<author><name sortKey="Cihlar, Tomas" sort="Cihlar, Tomas" uniqKey="Cihlar T" first="Tomas" last="Cihlar">Tomas Cihlar</name>
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<country xml:lang="fr">États-Unis</country>
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<placeName><region type="state">Californie</region>
</placeName>
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<author><name sortKey="Jordan, Robert" sort="Jordan, Robert" uniqKey="Jordan R" first="Robert" last="Jordan">Robert Jordan</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Gilead Sciences Inc., Foster City, CA 94404</wicri:regionArea>
<placeName><region type="state">Californie</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="2"><nlm:affiliation>Division of Infectious Diseases, Department of Pediatrics and Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. mark.denison@vanderbilt.edu rbaric@email.unc.edu.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Infectious Diseases, Department of Pediatrics and Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232</wicri:regionArea>
<placeName><region type="state">Tennessee</region>
</placeName>
</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. mark.denison@vanderbilt.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>
<placeName><region type="state">Caroline du Nord</region>
<settlement type="city">Chapel Hill (Caroline du Nord)</settlement>
</placeName>
<orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName>
</affiliation>
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<sourceDesc><biblStruct><analytic><title xml:lang="en">Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses.</title>
<author><name sortKey="Sheahan, Timothy P" sort="Sheahan, Timothy P" uniqKey="Sheahan T" first="Timothy P" last="Sheahan">Timothy P. Sheahan</name>
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</placeName>
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<author><name sortKey="Sims, Amy C" sort="Sims, Amy C" uniqKey="Sims A" first="Amy C" last="Sims">Amy C. Sims</name>
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<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>
<placeName><region type="state">Caroline du Nord</region>
<settlement type="city">Chapel Hill (Caroline du Nord)</settlement>
</placeName>
<orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName>
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<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>
<placeName><region type="state">Caroline du Nord</region>
<settlement type="city">Chapel Hill (Caroline du Nord)</settlement>
</placeName>
<orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName>
</affiliation>
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<author><name sortKey="Menachery, Vineet D" sort="Menachery, Vineet D" uniqKey="Menachery V" first="Vineet D" last="Menachery">Vineet D. Menachery</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>
<placeName><region type="state">Caroline du Nord</region>
<settlement type="city">Chapel Hill (Caroline du Nord)</settlement>
</placeName>
<orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName>
</affiliation>
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<author><name sortKey="Gralinski, Lisa E" sort="Gralinski, Lisa E" uniqKey="Gralinski L" first="Lisa E" last="Gralinski">Lisa E. Gralinski</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>
<placeName><region type="state">Caroline du Nord</region>
<settlement type="city">Chapel Hill (Caroline du Nord)</settlement>
</placeName>
<orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName>
</affiliation>
</author>
<author><name sortKey="Case, James B" sort="Case, James B" uniqKey="Case J" first="James B" last="Case">James B. Case</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232</wicri:regionArea>
<placeName><region type="state">Tennessee</region>
</placeName>
</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>
<placeName><region type="state">Caroline du Nord</region>
<settlement type="city">Chapel Hill (Caroline du Nord)</settlement>
</placeName>
<orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName>
</affiliation>
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<author><name sortKey="Pyrc, Krzysztof" sort="Pyrc, Krzysztof" uniqKey="Pyrc K" first="Krzysztof" last="Pyrc">Krzysztof Pyrc</name>
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<author><name sortKey="Clarke, Michael O" sort="Clarke, Michael O" uniqKey="Clarke M" first="Michael O" last="Clarke">Michael O. Clarke</name>
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<author><name sortKey="Siegel, Dustin" sort="Siegel, Dustin" uniqKey="Siegel D" first="Dustin" last="Siegel">Dustin Siegel</name>
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<author><name sortKey="Ray, Adrian S" sort="Ray, Adrian S" uniqKey="Ray A" first="Adrian S" last="Ray">Adrian S. Ray</name>
<affiliation wicri:level="2"><nlm:affiliation>Gilead Sciences Inc., Foster City, CA 94404, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Gilead Sciences Inc., Foster City, CA 94404</wicri:regionArea>
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<author><name sortKey="Cihlar, Tomas" sort="Cihlar, Tomas" uniqKey="Cihlar T" first="Tomas" last="Cihlar">Tomas Cihlar</name>
<affiliation wicri:level="2"><nlm:affiliation>Gilead Sciences Inc., Foster City, CA 94404, USA.</nlm:affiliation>
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<author><name sortKey="Jordan, Robert" sort="Jordan, Robert" uniqKey="Jordan R" first="Robert" last="Jordan">Robert Jordan</name>
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<wicri:regionArea>Gilead Sciences Inc., Foster City, CA 94404</wicri:regionArea>
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<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:affiliation>Division of Infectious Diseases, Department of Pediatrics and Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. mark.denison@vanderbilt.edu rbaric@email.unc.edu.</nlm:affiliation>
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<wicri:regionArea>Division of Infectious Diseases, Department of Pediatrics and Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232</wicri:regionArea>
<placeName><region type="state">Tennessee</region>
</placeName>
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<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. mark.denison@vanderbilt.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>
<placeName><region type="state">Caroline du Nord</region>
<settlement type="city">Chapel Hill (Caroline du Nord)</settlement>
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<series><title level="j">Science translational medicine</title>
<idno type="eISSN">1946-6242</idno>
<imprint><date when="2017" type="published">2017</date>
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<front><div type="abstract" xml:lang="en">Emerging viral infections are difficult to control because heterogeneous members periodically cycle in and out of humans and zoonotic hosts, complicating the development of specific antiviral therapies and vaccines. Coronaviruses (CoVs) have a proclivity to spread rapidly into new host species causing severe disease. Severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV) successively emerged, causing severe epidemic respiratory disease in immunologically naïve human populations throughout the globe. Broad-spectrum therapies capable of inhibiting CoV infections would address an immediate unmet medical need and could be invaluable in the treatment of emerging and endemic CoV infections. We show that a nucleotide prodrug, GS-5734, currently in clinical development for treatment of Ebola virus disease, can inhibit SARS-CoV and MERS-CoV replication in multiple in vitro systems, including primary human airway epithelial cell cultures with submicromolar IC<sub>50</sub>
 values. GS-5734 was also effective against bat CoVs, prepandemic bat CoVs, and circulating contemporary human CoV in primary human lung cells, thus demonstrating broad-spectrum anti-CoV activity. In a mouse model of SARS-CoV pathogenesis, prophylactic and early therapeutic administration of GS-5734 significantly reduced lung viral load and improved clinical signs of disease as well as respiratory function. These data provide substantive evidence that GS-5734 may prove effective against endemic MERS-CoV in the Middle East, circulating human CoV, and, possibly most importantly, emerging CoV of the future.</div>
</front>
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<name sortKey="Feng, Joy Y" sort="Feng, Joy Y" uniqKey="Feng J" first="Joy Y" last="Feng">Joy Y. Feng</name>
<name sortKey="Graham, Rachel L" sort="Graham, Rachel L" uniqKey="Graham R" first="Rachel L" last="Graham">Rachel L. Graham</name>
<name sortKey="Gralinski, Lisa E" sort="Gralinski, Lisa E" uniqKey="Gralinski L" first="Lisa E" last="Gralinski">Lisa E. Gralinski</name>
<name sortKey="Jordan, Robert" sort="Jordan, Robert" uniqKey="Jordan R" first="Robert" last="Jordan">Robert Jordan</name>
<name sortKey="Leist, Sarah R" sort="Leist, Sarah R" uniqKey="Leist S" first="Sarah R" last="Leist">Sarah R. Leist</name>
<name sortKey="Mackman, Richard L" sort="Mackman, Richard L" uniqKey="Mackman R" first="Richard L" last="Mackman">Richard L. Mackman</name>
<name sortKey="Menachery, Vineet D" sort="Menachery, Vineet D" uniqKey="Menachery V" first="Vineet D" last="Menachery">Vineet D. Menachery</name>
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<name sortKey="Trantcheva, Iva" sort="Trantcheva, Iva" uniqKey="Trantcheva I" first="Iva" last="Trantcheva">Iva Trantcheva</name>
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Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses.

Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses.

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