Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture.
Identifieur interne : 000F95 ( PubMed/Corpus ); précédent : 000F94; suivant : 000F96Screening 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 [ 1098-6596 ] ; 2014.
English descriptors
- KwdEn :
- Animals, Antiviral Agents (pharmacology), Cell Line, Chlorocebus aethiops, Chloroquine (pharmacology), Chlorpromazine (pharmacology), Coronavirus 229E, Human (drug effects), Coronavirus 229E, Human (physiology), Drug Approval, Hepatocytes (drug effects), Hepatocytes (pathology), Hepatocytes (virology), High-Throughput Screening Assays, Humans, Inhibitory Concentration 50, Loperamide (pharmacology), Lopinavir (pharmacology), Middle East Respiratory Syndrome Coronavirus (drug effects), Middle East Respiratory Syndrome Coronavirus (physiology), SARS Virus (drug effects), SARS Virus (physiology), Small Molecule Libraries (pharmacology), Vero Cells, Virus Replication (drug effects).
- MESH :
- chemical , pharmacology : Antiviral Agents, Chloroquine, Chlorpromazine, Loperamide, Lopinavir, Small Molecule Libraries.
- drug effects : Coronavirus 229E, Human, Hepatocytes, Middle East Respiratory Syndrome Coronavirus, SARS Virus, Virus Replication.
- pathology : Hepatocytes.
- physiology : Coronavirus 229E, Human, Middle East Respiratory Syndrome Coronavirus, SARS Virus.
- virology : Hepatocytes.
- Animals, Cell Line, Chlorocebus aethiops, Drug Approval, High-Throughput Screening Assays, Humans, Inhibitory Concentration 50, Vero Cells.
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 [EC(50)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.
DOI: 10.1128/AAC.03011-14
PubMed: 24841269
Links to Exploration step
pubmed:24841269Le document en format XML
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Posthuma</name><affiliation><nlm:affiliation>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Zevenhoven Dobbe, Jessika C" sort="Zevenhoven Dobbe, Jessika C" uniqKey="Zevenhoven Dobbe J" first="Jessika C" last="Zevenhoven-Dobbe">Jessika C. 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De Wilde</name><affiliation><nlm:affiliation>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Jochmans, Dirk" sort="Jochmans, Dirk" uniqKey="Jochmans D" first="Dirk" last="Jochmans">Dirk Jochmans</name><affiliation><nlm:affiliation>Rega Institute for Medical Research, KU, Leuven, Belgium.</nlm:affiliation></affiliation></author><author><name sortKey="Posthuma, Clara C" sort="Posthuma, Clara C" uniqKey="Posthuma C" first="Clara C" last="Posthuma">Clara C. Posthuma</name><affiliation><nlm:affiliation>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Zevenhoven Dobbe, Jessika C" sort="Zevenhoven Dobbe, Jessika C" uniqKey="Zevenhoven Dobbe J" first="Jessika C" last="Zevenhoven-Dobbe">Jessika C. 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Van Den Hoogen</name><affiliation><nlm:affiliation>Department of Viroscience, Erasmus Medical Center, Rotterdam, Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Neyts, Johan" sort="Neyts, Johan" uniqKey="Neyts J" first="Johan" last="Neyts">Johan Neyts</name><affiliation><nlm:affiliation>Rega Institute for Medical Research, KU, Leuven, Belgium Johan.Neyts@rega.kuleuven.be E.J.Snijder@LUMC.nl.</nlm:affiliation></affiliation></author><author><name sortKey="Snijder, Eric J" sort="Snijder, Eric J" uniqKey="Snijder E" first="Eric J" last="Snijder">Eric J. Snijder</name><affiliation><nlm:affiliation>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, Netherlands Johan.Neyts@rega.kuleuven.be E.J.Snijder@LUMC.nl.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Antimicrobial agents and chemotherapy</title><idno type="eISSN">1098-6596</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Antiviral Agents (pharmacology)</term><term>Cell Line</term><term>Chlorocebus aethiops</term><term>Chloroquine (pharmacology)</term><term>Chlorpromazine (pharmacology)</term><term>Coronavirus 229E, Human (drug effects)</term><term>Coronavirus 229E, Human (physiology)</term><term>Drug Approval</term><term>Hepatocytes (drug effects)</term><term>Hepatocytes (pathology)</term><term>Hepatocytes (virology)</term><term>High-Throughput Screening Assays</term><term>Humans</term><term>Inhibitory Concentration 50</term><term>Loperamide (pharmacology)</term><term>Lopinavir (pharmacology)</term><term>Middle East Respiratory Syndrome Coronavirus (drug effects)</term><term>Middle East Respiratory Syndrome Coronavirus (physiology)</term><term>SARS Virus (drug effects)</term><term>SARS Virus (physiology)</term><term>Small Molecule Libraries (pharmacology)</term><term>Vero Cells</term><term>Virus Replication (drug effects)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term><term>Chloroquine</term><term>Chlorpromazine</term><term>Loperamide</term><term>Lopinavir</term><term>Small Molecule Libraries</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Coronavirus 229E, Human</term><term>Hepatocytes</term><term>Middle East Respiratory Syndrome Coronavirus</term><term>SARS Virus</term><term>Virus Replication</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Hepatocytes</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Coronavirus 229E, Human</term><term>Middle East Respiratory Syndrome Coronavirus</term><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Hepatocytes</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cell Line</term><term>Chlorocebus aethiops</term><term>Drug Approval</term><term>High-Throughput Screening Assays</term><term>Humans</term><term>Inhibitory Concentration 50</term><term>Vero Cells</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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(50)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.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">24841269</PMID><DateCompleted><Year>2015</Year><Month>09</Month><Day>14</Day></DateCompleted><DateRevised><Year>2019</Year><Month>12</Month><Day>10</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1098-6596</ISSN><JournalIssue CitedMedium="Internet"><Volume>58</Volume><Issue>8</Issue><PubDate><Year>2014</Year><Month>Aug</Month></PubDate></JournalIssue><Title>Antimicrobial agents and chemotherapy</Title><ISOAbbreviation>Antimicrob. Agents Chemother.</ISOAbbreviation></Journal><ArticleTitle>Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture.</ArticleTitle><Pagination><MedlinePgn>4875-84</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1128/AAC.03011-14</ELocationID><Abstract><AbstractText>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(50)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.</AbstractText><CopyrightInformation>Copyright © 2014, American Society for Microbiology. All Rights Reserved.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>de Wilde</LastName><ForeName>Adriaan H</ForeName><Initials>AH</Initials><AffiliationInfo><Affiliation>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Jochmans</LastName><ForeName>Dirk</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Rega Institute for Medical Research, KU, Leuven, Belgium.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Posthuma</LastName><ForeName>Clara C</ForeName><Initials>CC</Initials><AffiliationInfo><Affiliation>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zevenhoven-Dobbe</LastName><ForeName>Jessika C</ForeName><Initials>JC</Initials><AffiliationInfo><Affiliation>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>van Nieuwkoop</LastName><ForeName>Stefan</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Department of Viroscience, Erasmus Medical Center, Rotterdam, Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bestebroer</LastName><ForeName>Theo M</ForeName><Initials>TM</Initials><AffiliationInfo><Affiliation>Department of Viroscience, Erasmus Medical Center, Rotterdam, Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>van den Hoogen</LastName><ForeName>Bernadette G</ForeName><Initials>BG</Initials><AffiliationInfo><Affiliation>Department of Viroscience, Erasmus Medical Center, Rotterdam, Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Neyts</LastName><ForeName>Johan</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Rega Institute for Medical Research, KU, Leuven, Belgium Johan.Neyts@rega.kuleuven.be E.J.Snijder@LUMC.nl.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Snijder</LastName><ForeName>Eric J</ForeName><Initials>EJ</Initials><AffiliationInfo><Affiliation>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, Netherlands Johan.Neyts@rega.kuleuven.be E.J.Snijder@LUMC.nl.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2014</Year><Month>05</Month><Day>19</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Antimicrob Agents Chemother</MedlineTA><NlmUniqueID>0315061</NlmUniqueID><ISSNLinking>0066-4804</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000998">Antiviral Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D054852">Small Molecule Libraries</NameOfSubstance></Chemical><Chemical><RegistryNumber>2494G1JF75</RegistryNumber><NameOfSubstance UI="D061466">Lopinavir</NameOfSubstance></Chemical><Chemical><RegistryNumber>6X9OC3H4II</RegistryNumber><NameOfSubstance UI="D008139">Loperamide</NameOfSubstance></Chemical><Chemical><RegistryNumber>886U3H6UFF</RegistryNumber><NameOfSubstance UI="D002738">Chloroquine</NameOfSubstance></Chemical><Chemical><RegistryNumber>U42B7VYA4P</RegistryNumber><NameOfSubstance UI="D002746">Chlorpromazine</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000998" MajorTopicYN="N">Antiviral Agents</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002460" MajorTopicYN="N">Cell Line</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002522" MajorTopicYN="N">Chlorocebus aethiops</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002738" MajorTopicYN="N">Chloroquine</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002746" MajorTopicYN="N">Chlorpromazine</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D028941" 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UI="D008139" MajorTopicYN="N">Loperamide</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D061466" MajorTopicYN="N">Lopinavir</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D065207" MajorTopicYN="N">Middle East Respiratory Syndrome Coronavirus</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D045473" MajorTopicYN="N">SARS Virus</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D054852" MajorTopicYN="N">Small Molecule Libraries</DescriptorName><QualifierName UI="Q000494" 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