MersV1, PubMed, Corpus, bibRecord, 000C39

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

Identifieur interne : 000C39 ( PubMed/Corpus ); précédent : 000C38; suivant : 000C40

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

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

Source :

Science translational medicine [ 1946-6242 ] ; 2017.

RBID : pubmed:28659436

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

Links to Exploration step

pubmed:28659436

Le document en format XML

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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>
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<DateCompleted><Year>2018</Year>
<Month>03</Month>
<Day>30</Day>
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<DateRevised><Year>2020</Year>
<Month>03</Month>
<Day>16</Day>
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<Issue>396</Issue>
<PubDate><Year>2017</Year>
<Month>06</Month>
<Day>28</Day>
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<ArticleTitle>Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses.</ArticleTitle>
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<Abstract><AbstractText>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.</AbstractText>
<CopyrightInformation>Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Sheahan</LastName>
<ForeName>Timothy P</ForeName>
<Initials>TP</Initials>
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<AffiliationInfo><Affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.</Affiliation>
</AffiliationInfo>
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<Author ValidYN="Y"><LastName>Sims</LastName>
<ForeName>Amy C</ForeName>
<Initials>AC</Initials>
<Identifier Source="ORCID">0000-0003-0178-4225</Identifier>
<AffiliationInfo><Affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Graham</LastName>
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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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