SrasV1, Main, Exploration, bibRecord, 000E68

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

Identifieur interne : 000E68 ( Main/Exploration ); précédent : 000E67; suivant : 000E69

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 [ 1946-6234 ] ; 2017.

RBID : PMC:5567817

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 as 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. SARS-CoV and 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. Here 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 functions. 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.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567817

DOI: 10.1126/scitranslmed.aal3653
PubMed: 28659436
PubMed Central: 5567817

Affiliations:

Le document en format XML

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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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<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="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="A3">Department of Pediatrics-Infectious Diseases, Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Tennessee</region>
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<wicri:cityArea>Department of Pediatrics-Infectious Diseases, Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville</wicri:cityArea>
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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>
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<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Caroline du Nord</region>
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<wicri:cityArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill</wicri:cityArea>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses</title>
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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>
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<author><name sortKey="Case, James B" sort="Case, James B" uniqKey="Case J" first="James B." last="Case">James B. Case</name>
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<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Tennessee</region>
</placeName>
<wicri:cityArea>Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville</wicri:cityArea>
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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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<country xml:lang="fr">États-Unis</country>
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<wicri:cityArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill</wicri:cityArea>
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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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<country xml:lang="fr">Pologne</country>
<wicri:regionArea>Department of Microbiology, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University, Krakow</wicri:regionArea>
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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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<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="Trantcheva, Iva" sort="Trantcheva, Iva" uniqKey="Trantcheva I" first="Iva" last="Trantcheva">Iva Trantcheva</name>
<affiliation wicri:level="2"><nlm:aff id="A2">Gilead Sciences, Inc., Foster City, CA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
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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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<placeName><region type="state">Californie</region>
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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><region type="state">Californie</region>
</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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<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Californie</region>
</placeName>
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<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Californie</region>
</placeName>
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</affiliation>
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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>
<affiliation wicri:level="2"><nlm:aff id="A2">Gilead Sciences, Inc., Foster City, CA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Californie</region>
</placeName>
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</author>
<author><name sortKey="Palmiotti, Christopher A" sort="Palmiotti, Christopher A" uniqKey="Palmiotti C" first="Christopher A." last="Palmiotti">Christopher A. Palmiotti</name>
<affiliation wicri:level="2"><nlm:aff id="A2">Gilead Sciences, Inc., Foster City, CA</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="Siegel, Dustin" sort="Siegel, Dustin" uniqKey="Siegel D" first="Dustin" last="Siegel">Dustin Siegel</name>
<affiliation wicri:level="2"><nlm:aff id="A2">Gilead Sciences, Inc., Foster City, CA</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="Ray, Adrian S" sort="Ray, Adrian S" uniqKey="Ray A" first="Adrian S." last="Ray">Adrian S. Ray</name>
<affiliation wicri:level="2"><nlm:aff id="A2">Gilead Sciences, Inc., Foster City, CA</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="Cihlar, Tomas" sort="Cihlar, Tomas" uniqKey="Cihlar T" first="Tomas" last="Cihlar">Tomas Cihlar</name>
<affiliation wicri:level="2"><nlm:aff id="A2">Gilead Sciences, Inc., Foster City, CA</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="Jordan, Robert" sort="Jordan, Robert" uniqKey="Jordan R" first="Robert" last="Jordan">Robert Jordan</name>
<affiliation wicri:level="2"><nlm:aff id="A2">Gilead Sciences, Inc., Foster City, CA</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="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="A3">Department of Pediatrics-Infectious Diseases, Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Tennessee</region>
</placeName>
<wicri:cityArea>Department of Pediatrics-Infectious Diseases, Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, 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="A1">Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Caroline du Nord</region>
</placeName>
<wicri:cityArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill</wicri:cityArea>
</affiliation>
</author>
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<series><title level="j">Science translational medicine</title>
<idno type="ISSN">1946-6234</idno>
<idno type="eISSN">1946-6242</idno>
<imprint><date when="2017">2017</date>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Alanine (analogs & derivatives)</term>
<term>Alanine (metabolism)</term>
<term>Alanine (pharmacokinetics)</term>
<term>Alanine (pharmacology)</term>
<term>Alanine (toxicity)</term>
<term>Animals</term>
<term>Antiviral Agents (metabolism)</term>
<term>Antiviral Agents (pharmacokinetics)</term>
<term>Antiviral Agents (pharmacology)</term>
<term>Antiviral Agents (toxicity)</term>
<term>Callithrix</term>
<term>Cell Line</term>
<term>Coronavirus (drug effects)</term>
<term>Epidemics</term>
<term>Epithelial Cells (virology)</term>
<term>Humans</term>
<term>Lung (pathology)</term>
<term>Mice</term>
<term>Ribonucleotides (metabolism)</term>
<term>Ribonucleotides (pharmacokinetics)</term>
<term>Ribonucleotides (pharmacology)</term>
<term>Ribonucleotides (toxicity)</term>
<term>Virus Replication (drug effects)</term>
<term>Zoonoses (epidemiology)</term>
<term>Zoonoses (prevention & control)</term>
<term>Zoonoses (virology)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Alanine (analogues et dérivés)</term>
<term>Alanine (métabolisme)</term>
<term>Alanine (pharmacocinétique)</term>
<term>Alanine (pharmacologie)</term>
<term>Alanine (toxicité)</term>
<term>Animaux</term>
<term>Antiviraux (métabolisme)</term>
<term>Antiviraux (pharmacocinétique)</term>
<term>Antiviraux (pharmacologie)</term>
<term>Antiviraux (toxicité)</term>
<term>Callithrix</term>
<term>Cellules épithéliales (virologie)</term>
<term>Coronavirus ()</term>
<term>Humains</term>
<term>Lignée cellulaire</term>
<term>Poumon (anatomopathologie)</term>
<term>Ribonucléotides (métabolisme)</term>
<term>Ribonucléotides (pharmacocinétique)</term>
<term>Ribonucléotides (pharmacologie)</term>
<term>Ribonucléotides (toxicité)</term>
<term>Réplication virale ()</term>
<term>Souris</term>
<term>Zoonoses ()</term>
<term>Zoonoses (virologie)</term>
<term>Zoonoses (épidémiologie)</term>
<term>Épidémies</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en"><term>Alanine</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Alanine</term>
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<term>Ribonucleotides</term>
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<keywords scheme="MESH" type="chemical" qualifier="pharmacokinetics" xml:lang="en"><term>Alanine</term>
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<term>Antiviral Agents</term>
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<term>Antiviral Agents</term>
<term>Ribonucleotides</term>
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<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Poumon</term>
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<term>Zoonoses</term>
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<keywords scheme="MESH" qualifier="épidémiologie" xml:lang="fr"><term>Zoonoses</term>
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<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Callithrix</term>
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<term>Epidemics</term>
<term>Humans</term>
<term>Mice</term>
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<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Callithrix</term>
<term>Coronavirus</term>
<term>Humains</term>
<term>Lignée cellulaire</term>
<term>Réplication virale</term>
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<front><div type="abstract" xml:lang="en"><p id="P1">Emerging viral infections are difficult to control as 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. SARS-CoV and 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. Here 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 functions. 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.</p>
</div>
</front>
</TEI>
<affiliations><list><country><li>Pologne</li>
<li>États-Unis</li>
</country>
<region><li>Californie</li>
<li>Caroline du Nord</li>
<li>Tennessee</li>
</region>
</list>
<tree><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="Babusis, Darius" sort="Babusis, Darius" uniqKey="Babusis D" first="Darius" last="Babusis">Darius Babusis</name>
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<name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S." last="Baric">Ralph S. Baric</name>
<name sortKey="Case, James B" sort="Case, James B" uniqKey="Case J" first="James B." last="Case">James B. Case</name>
<name sortKey="Cihlar, Tomas" sort="Cihlar, Tomas" uniqKey="Cihlar T" first="Tomas" last="Cihlar">Tomas Cihlar</name>
<name sortKey="Clarke, Michael O" sort="Clarke, Michael O" uniqKey="Clarke M" first="Michael O." last="Clarke">Michael O. Clarke</name>
<name sortKey="Denison, Mark R" sort="Denison, Mark R" uniqKey="Denison M" first="Mark R." last="Denison">Mark R. Denison</name>
<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>
<name sortKey="Palmiotti, Christopher A" sort="Palmiotti, Christopher A" uniqKey="Palmiotti C" first="Christopher A." last="Palmiotti">Christopher A. Palmiotti</name>
<name sortKey="Park, Yeojin" sort="Park, Yeojin" uniqKey="Park Y" first="Yeojin" last="Park">Yeojin Park</name>
<name sortKey="Ray, Adrian S" sort="Ray, Adrian S" uniqKey="Ray A" first="Adrian S." last="Ray">Adrian S. Ray</name>
<name sortKey="Siegel, Dustin" sort="Siegel, Dustin" uniqKey="Siegel D" first="Dustin" last="Siegel">Dustin Siegel</name>
<name sortKey="Sims, Amy C" sort="Sims, Amy C" uniqKey="Sims A" first="Amy C." last="Sims">Amy C. Sims</name>
<name sortKey="Spahn, Jamie E" sort="Spahn, Jamie E" uniqKey="Spahn J" first="Jamie E." last="Spahn">Jamie E. Spahn</name>
<name sortKey="Trantcheva, Iva" sort="Trantcheva, Iva" uniqKey="Trantcheva I" first="Iva" last="Trantcheva">Iva Trantcheva</name>
</country>
<country name="Pologne"><noRegion><name sortKey="Pyrc, Krzysztof" sort="Pyrc, Krzysztof" uniqKey="Pyrc K" first="Krzysztof" last="Pyrc">Krzysztof Pyrc</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>

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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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