Screening of an FDA-Approved Compound Library Identifies Four Small-Molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Replication in Cell Culture
Identifieur interne : 000C39 ( Pmc/Corpus ); précédent : 000C38; suivant : 000C40Screening of an FDA-Approved Compound Library Identifies Four Small-Molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Replication in Cell Culture
Auteurs : Adriaan H. De Wilde ; Dirk Jochmans ; Clara C. Posthuma ; Jessika C. Zevenhoven-Dobbe ; Stefan Van Nieuwkoop ; Theo M. Bestebroer ; Bernadette G. Van Den Hoogen ; Johan Neyts ; Eric J. SnijderSource :
- Antimicrobial Agents and Chemotherapy [ 0066-4804 ] ; 2014.
Abstract
Coronaviruses can cause respiratory and enteric disease in a wide variety of human and animal hosts. The 2003 outbreak of severe acute respiratory syndrome (SARS) first demonstrated the potentially lethal consequences of zoonotic coronavirus infections in humans. In 2012, a similar previously unknown coronavirus emerged, Middle East respiratory syndrome coronavirus (MERS-CoV), thus far causing over 650 laboratory-confirmed infections, with an unexplained steep rise in the number of cases being recorded over recent months. The human MERS fatality rate of ∼30% is alarmingly high, even though many deaths were associated with underlying medical conditions. Registered therapeutics for the treatment of coronavirus infections are not available. Moreover, the pace of drug development and registration for human use is generally incompatible with strategies to combat emerging infectious diseases. Therefore, we have screened a library of 348 FDA-approved drugs for anti-MERS-CoV activity in cell culture. If such compounds proved sufficiently potent, their efficacy might be directly assessed in MERS patients. We identified four compounds (chloroquine, chlorpromazine, loperamide, and lopinavir) inhibiting MERS-CoV replication in the low-micromolar range (50% effective concentrations [EC50s], 3 to 8 μM). Moreover, these compounds also inhibit the replication of SARS coronavirus and human coronavirus 229E. Although their protective activity (alone or in combination) remains to be assessed in animal models, our findings may offer a starting point for treatment of patients infected with zoonotic coronaviruses like MERS-CoV. Although they may not necessarily reduce viral replication to very low levels, a moderate viral load reduction may create a window during which to mount a protective immune response.
Url:
DOI: 10.1128/AAC.03011-14
PubMed: 24841269
PubMed Central: 4136071
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<front><div type="abstract" xml:lang="en"><p>Coronaviruses can cause respiratory and enteric disease in a wide variety of human and animal hosts. The 2003 outbreak of severe acute respiratory syndrome (SARS) first demonstrated the potentially lethal consequences of zoonotic coronavirus infections in humans. In 2012, a similar previously unknown coronavirus emerged, Middle East respiratory syndrome coronavirus (MERS-CoV), thus far causing over 650 laboratory-confirmed infections, with an unexplained steep rise in the number of cases being recorded over recent months. The human MERS fatality rate of ∼30% is alarmingly high, even though many deaths were associated with underlying medical conditions. Registered therapeutics for the treatment of coronavirus infections are not available. Moreover, the pace of drug development and registration for human use is generally incompatible with strategies to combat emerging infectious diseases. Therefore, we have screened a library of 348 FDA-approved drugs for anti-MERS-CoV activity in cell culture. If such compounds proved sufficiently potent, their efficacy might be directly assessed in MERS patients. We identified four compounds (chloroquine, chlorpromazine, loperamide, and lopinavir) inhibiting MERS-CoV replication in the low-micromolar range (50% effective concentrations [EC<sub>50</sub>
s], 3 to 8 μM). Moreover, these compounds also inhibit the replication of SARS coronavirus and human coronavirus 229E. Although their protective activity (alone or in combination) remains to be assessed in animal models, our findings may offer a starting point for treatment of patients infected with zoonotic coronaviruses like MERS-CoV. Although they may not necessarily reduce viral replication to very low levels, a moderate viral load reduction may create a window during which to mount a protective immune response.</p>
</div>
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<front><journal-meta><journal-id journal-id-type="nlm-ta">Antimicrob Agents Chemother</journal-id>
<journal-id journal-id-type="iso-abbrev">Antimicrob. Agents Chemother</journal-id>
<journal-id journal-id-type="hwp">aac</journal-id>
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<article-id pub-id-type="doi">10.1128/AAC.03011-14</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Antiviral Agents</subject>
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<title-group><article-title>Screening of an FDA-Approved Compound Library Identifies Four Small-Molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Replication in Cell Culture</article-title>
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<contrib-group><contrib contrib-type="author"><name><surname>de Wilde</surname>
<given-names>Adriaan H.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Jochmans</surname>
<given-names>Dirk</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Posthuma</surname>
<given-names>Clara C.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zevenhoven-Dobbe</surname>
<given-names>Jessika C.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>van Nieuwkoop</surname>
<given-names>Stefan</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>c</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bestebroer</surname>
<given-names>Theo M.</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>c</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>van den Hoogen</surname>
<given-names>Bernadette G.</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>c</sup>
</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Neyts</surname>
<given-names>Johan</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Snijder</surname>
<given-names>Eric J.</given-names>
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<xref ref-type="aff" rid="aff1"><sup>a</sup>
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</contrib>
<aff id="aff1"><label>a</label>
Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, Netherlands</aff>
<aff id="aff2"><label>b</label>
Rega Institute for Medical Research, KU, Leuven, Belgium</aff>
<aff id="aff3"><label>c</label>
Department of Viroscience, Erasmus Medical Center, Rotterdam, Netherlands</aff>
</contrib-group>
<author-notes><corresp id="cor1">Address correspondence to Johan Neyts, <email>Johan.Neyts@rega.kuleuven.be</email>
, or Eric. J. Snijder, <email>E.J.Snijder@LUMC.nl</email>
.</corresp>
<fn fn-type="equal"><p>A.H.D.W. and D.J. contributed equally to this article.</p>
</fn>
<fn fn-type="equal"><p>J.N. and E.J.S. contributed equally to this article.</p>
</fn>
</author-notes>
<pub-date pub-type="ppub"><month>8</month>
<year>2014</year>
</pub-date>
<volume>58</volume>
<issue>8</issue>
<fpage>4875</fpage>
<lpage>4884</lpage>
<history><date date-type="received"><day>10</day>
<month>4</month>
<year>2014</year>
</date>
<date date-type="rev-request"><day>2</day>
<month>5</month>
<year>2014</year>
</date>
<date date-type="accepted"><day>14</day>
<month>5</month>
<year>2014</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2014, American Society for Microbiology. All Rights Reserved.</copyright-statement>
<copyright-year>2014</copyright-year>
<copyright-holder>American Society for Microbiology</copyright-holder>
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<abstract><p>Coronaviruses can cause respiratory and enteric disease in a wide variety of human and animal hosts. The 2003 outbreak of severe acute respiratory syndrome (SARS) first demonstrated the potentially lethal consequences of zoonotic coronavirus infections in humans. In 2012, a similar previously unknown coronavirus emerged, Middle East respiratory syndrome coronavirus (MERS-CoV), thus far causing over 650 laboratory-confirmed infections, with an unexplained steep rise in the number of cases being recorded over recent months. The human MERS fatality rate of ∼30% is alarmingly high, even though many deaths were associated with underlying medical conditions. Registered therapeutics for the treatment of coronavirus infections are not available. Moreover, the pace of drug development and registration for human use is generally incompatible with strategies to combat emerging infectious diseases. Therefore, we have screened a library of 348 FDA-approved drugs for anti-MERS-CoV activity in cell culture. If such compounds proved sufficiently potent, their efficacy might be directly assessed in MERS patients. We identified four compounds (chloroquine, chlorpromazine, loperamide, and lopinavir) inhibiting MERS-CoV replication in the low-micromolar range (50% effective concentrations [EC<sub>50</sub>
s], 3 to 8 μM). Moreover, these compounds also inhibit the replication of SARS coronavirus and human coronavirus 229E. Although their protective activity (alone or in combination) remains to be assessed in animal models, our findings may offer a starting point for treatment of patients infected with zoonotic coronaviruses like MERS-CoV. Although they may not necessarily reduce viral replication to very low levels, a moderate viral load reduction may create a window during which to mount a protective immune response.</p>
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