Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus
Identifieur interne : 002069 ( Main/Merge ); précédent : 002068; suivant : 002070Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus
Auteurs : Jasper F. W. Chan [République populaire de Chine] ; Kwok-Hung Chan [République populaire de Chine] ; Richard Y. T. Kao [République populaire de Chine] ; Kelvin K. W. To [République populaire de Chine] ; Bo-Jian Zheng [République populaire de Chine] ; Clara P. Y. Li [République populaire de Chine] ; Patrick T. W. Li [République populaire de Chine] ; Jun Dai [République populaire de Chine] ; Florence K. Y. Mok [République populaire de Chine] ; Honglin Chen [République populaire de Chine] ; Frederick G. Hayden [États-Unis] ; Kwok-Yung Yuen [République populaire de Chine]Source :
- The Journal of Infection [ 0163-4453 ] ; 2013.
Descripteurs français
- KwdFr :
- Acide mycophénolique (pharmacologie), Animaux, Antiviraux (pharmacologie), Cellules Vero, Charge virale (), Coronavirus (), Découverte de médicament (), Flambées de maladies, Humains, Infections à coronavirus (traitement médicamenteux), Infections à coronavirus (virologie), Interférons (pharmacologie), Maladies transmissibles émergentes (traitement médicamenteux), Maladies transmissibles émergentes (virologie), Méthode des plages virales, Ribavirine (pharmacologie), Tests de criblage à haut débit ().
- MESH :
- pharmacologie : Acide mycophénolique, Antiviraux, Interférons, Ribavirine.
- traitement médicamenteux : Infections à coronavirus, Maladies transmissibles émergentes.
- virologie : Infections à coronavirus, Maladies transmissibles émergentes.
- Animaux, Cellules Vero, Charge virale, Coronavirus, Découverte de médicament, Flambées de maladies, Humains, Méthode des plages virales, Tests de criblage à haut débit.
English descriptors
- KwdEn :
- Animals, Antiviral Agents (pharmacology), Chlorocebus aethiops, Communicable Diseases, Emerging (drug therapy), Communicable Diseases, Emerging (virology), Coronavirus (drug effects), Coronavirus Infections (drug therapy), Coronavirus Infections (virology), Disease Outbreaks, Drug Discovery (methods), High-Throughput Screening Assays (methods), Humans, Interferons (pharmacology), Mycophenolic Acid (pharmacology), Ribavirin (pharmacology), Vero Cells, Viral Load (drug effects), Viral Plaque Assay.
- MESH :
- chemical , pharmacology : Antiviral Agents, Interferons, Mycophenolic Acid, Ribavirin.
- drug effects : Coronavirus, Viral Load.
- drug therapy : Communicable Diseases, Emerging, Coronavirus Infections.
- methods : Drug Discovery, High-Throughput Screening Assays.
- virology : Communicable Diseases, Emerging, Coronavirus Infections.
- Animals, Chlorocebus aethiops, Disease Outbreaks, Humans, Vero Cells, Viral Plaque Assay.
Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) has emerged to cause fatal infections in patients in the Middle East and traveler-associated secondary cases in Europe and Africa. Person-to-person transmission is evident in outbreaks involving household and hospital contacts. Effective antivirals are urgently needed.
We used small compound-based forward chemical genetics to screen a chemical library of 1280 known drugs against influenza A virus in Biosafety Level-2 laboratory. We then assessed the anti-MERS-CoV activities of the identified compounds and of interferons, nelfinavir, and lopinavir because of their reported anti-coronavirus activities in terms of cytopathic effect inhibition, viral yield reduction, and plaque reduction assays in Biosafety Level-3 laboratory.
Ten compounds were identified as primary hits in high-throughput screening. Only mycophenolic acid exhibited low EC50 and high selectivity index. Additionally, ribavirin and interferons also exhibited
Interferon-β1b with mycophenolic acid should be considered in treatment trials of MERS.
Url:
DOI: 10.1016/j.jinf.2013.09.029
PubMed: 24096239
PubMed Central: 7112612
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PMC:7112612Le document en format XML
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<affiliation wicri:level="1"><nlm:aff id="aff2">Department of Microbiology, The University of Hong Kong, Hong Kong, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Microbiology, The University of Hong Kong, Hong Kong</wicri:regionArea>
<wicri:noRegion>Hong Kong</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Mok, Florence K Y" sort="Mok, Florence K Y" uniqKey="Mok F" first="Florence K. Y." last="Mok">Florence K. Y. Mok</name>
<affiliation wicri:level="1"><nlm:aff id="aff2">Department of Microbiology, The University of Hong Kong, Hong Kong, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Microbiology, The University of Hong Kong, Hong Kong</wicri:regionArea>
<wicri:noRegion>Hong Kong</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Chen, Honglin" sort="Chen, Honglin" uniqKey="Chen H" first="Honglin" last="Chen">Honglin Chen</name>
<affiliation wicri:level="1"><nlm:aff id="aff1">State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong</wicri:regionArea>
<wicri:noRegion>Hong Kong</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2">Department of Microbiology, The University of Hong Kong, Hong Kong, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Microbiology, The University of Hong Kong, Hong Kong</wicri:regionArea>
<wicri:noRegion>Hong Kong</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff3">Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong</wicri:regionArea>
<wicri:noRegion>Hong Kong</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Hayden, Frederick G" sort="Hayden, Frederick G" uniqKey="Hayden F" first="Frederick G." last="Hayden">Frederick G. Hayden</name>
<affiliation wicri:level="2"><nlm:aff id="aff4">Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA</wicri:regionArea>
<placeName><region type="state">Virginie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Yuen, Kwok Yung" sort="Yuen, Kwok Yung" uniqKey="Yuen K" first="Kwok-Yung" last="Yuen">Kwok-Yung Yuen</name>
<affiliation wicri:level="1"><nlm:aff id="aff1">State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong</wicri:regionArea>
<wicri:noRegion>Hong Kong</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2">Department of Microbiology, The University of Hong Kong, Hong Kong, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Microbiology, The University of Hong Kong, Hong Kong</wicri:regionArea>
<wicri:noRegion>Hong Kong</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff3">Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong</wicri:regionArea>
<wicri:noRegion>Hong Kong</wicri:noRegion>
</affiliation>
</author>
</analytic>
<series><title level="j">The Journal of Infection</title>
<idno type="ISSN">0163-4453</idno>
<idno type="eISSN">1532-2742</idno>
<imprint><date when="2013">2013</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term>
<term>Antiviral Agents (pharmacology)</term>
<term>Chlorocebus aethiops</term>
<term>Communicable Diseases, Emerging (drug therapy)</term>
<term>Communicable Diseases, Emerging (virology)</term>
<term>Coronavirus (drug effects)</term>
<term>Coronavirus Infections (drug therapy)</term>
<term>Coronavirus Infections (virology)</term>
<term>Disease Outbreaks</term>
<term>Drug Discovery (methods)</term>
<term>High-Throughput Screening Assays (methods)</term>
<term>Humans</term>
<term>Interferons (pharmacology)</term>
<term>Mycophenolic Acid (pharmacology)</term>
<term>Ribavirin (pharmacology)</term>
<term>Vero Cells</term>
<term>Viral Load (drug effects)</term>
<term>Viral Plaque Assay</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Acide mycophénolique (pharmacologie)</term>
<term>Animaux</term>
<term>Antiviraux (pharmacologie)</term>
<term>Cellules Vero</term>
<term>Charge virale ()</term>
<term>Coronavirus ()</term>
<term>Découverte de médicament ()</term>
<term>Flambées de maladies</term>
<term>Humains</term>
<term>Infections à coronavirus (traitement médicamenteux)</term>
<term>Infections à coronavirus (virologie)</term>
<term>Interférons (pharmacologie)</term>
<term>Maladies transmissibles émergentes (traitement médicamenteux)</term>
<term>Maladies transmissibles émergentes (virologie)</term>
<term>Méthode des plages virales</term>
<term>Ribavirine (pharmacologie)</term>
<term>Tests de criblage à haut débit ()</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term>
<term>Interferons</term>
<term>Mycophenolic Acid</term>
<term>Ribavirin</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Coronavirus</term>
<term>Viral Load</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Communicable Diseases, Emerging</term>
<term>Coronavirus Infections</term>
</keywords>
<keywords scheme="MESH" qualifier="methods" xml:lang="en"><term>Drug Discovery</term>
<term>High-Throughput Screening Assays</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Acide mycophénolique</term>
<term>Antiviraux</term>
<term>Interférons</term>
<term>Ribavirine</term>
</keywords>
<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Infections à coronavirus</term>
<term>Maladies transmissibles émergentes</term>
</keywords>
<keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Infections à coronavirus</term>
<term>Maladies transmissibles émergentes</term>
</keywords>
<keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Communicable Diseases, Emerging</term>
<term>Coronavirus Infections</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Chlorocebus aethiops</term>
<term>Disease Outbreaks</term>
<term>Humans</term>
<term>Vero Cells</term>
<term>Viral Plaque Assay</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Cellules Vero</term>
<term>Charge virale</term>
<term>Coronavirus</term>
<term>Découverte de médicament</term>
<term>Flambées de maladies</term>
<term>Humains</term>
<term>Méthode des plages virales</term>
<term>Tests de criblage à haut débit</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><title>Summary</title>
<sec><title>Objectives</title>
<p>Middle East respiratory syndrome coronavirus (MERS-CoV) has emerged to cause fatal infections in patients in the Middle East and traveler-associated secondary cases in Europe and Africa. Person-to-person transmission is evident in outbreaks involving household and hospital contacts. Effective antivirals are urgently needed.</p>
</sec>
<sec><title>Methods</title>
<p>We used small compound-based forward chemical genetics to screen a chemical library of 1280 known drugs against influenza A virus in Biosafety Level-2 laboratory. We then assessed the anti-MERS-CoV activities of the identified compounds and of interferons, nelfinavir, and lopinavir because of their reported anti-coronavirus activities in terms of cytopathic effect inhibition, viral yield reduction, and plaque reduction assays in Biosafety Level-3 laboratory.</p>
</sec>
<sec><title>Results</title>
<p>Ten compounds were identified as primary hits in high-throughput screening. Only mycophenolic acid exhibited low EC<sub>50</sub>
and high selectivity index. Additionally, ribavirin and interferons also exhibited <italic>in-vitro</italic>
anti-MERS-CoV activity. The serum concentrations achievable at therapeutic doses of mycophenolic acid and interferon-β1b were 60–300 and 3–4 times higher than the concentrations at which <italic>in-vitro</italic>
anti-MERS-CoV activities were demonstrated, whereas that of ribavirin was ∼2 times lower. Combination of mycophenolic acid and interferon-β1b lowered the EC<sub>50</sub>
of each drug by 1–3 times.</p>
</sec>
<sec><title>Conclusions</title>
<p>Interferon-β1b with mycophenolic acid should be considered in treatment trials of MERS.</p>
</sec>
</div>
</front>
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