SrasV1, Main, Exploration, bibRecord, 001783

Screening of an FDA-Approved Compound Library Identifies Four Small-Molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Replication in Cell Culture

Identifieur interne : 001783 ( Main/Exploration ); précédent : 001782; suivant : 001784

Screening 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 [Pays-Bas] ; Dirk Jochmans [Belgique] ; Clara C. Posthuma [Pays-Bas] ; Jessika C. Zevenhoven-Dobbe [Pays-Bas] ; Stefan Van Nieuwkoop [Pays-Bas] ; Theo M. Bestebroer [Pays-Bas] ; Bernadette G. Van Den Hoogen [Pays-Bas] ; Johan Neyts [Belgique] ; Eric J. Snijder [Pays-Bas]

Source :

Antimicrobial agents and chemotherapy [ 0066-4804 ] ; 2014.

RBID : Pascal:14-0220020

Descripteurs français

KwdFr :
- Agrément de médicaments, Animaux, Antiviraux (pharmacologie), Bibliothèques de petites molécules (pharmacologie), Cellules Vero, Chloroquine (pharmacologie), Chlorpromazine (pharmacologie), Concentration inhibitrice 50, Coronavirus du syndrome respiratoire du Moyen-Orient (), Coronavirus du syndrome respiratoire du Moyen-Orient (physiologie), Coronavirus humain 229E (), Coronavirus humain 229E (physiologie), Humains, Hépatocytes (), Hépatocytes (anatomopathologie), Hépatocytes (virologie), Lignée cellulaire, Lopinavir (pharmacologie), Lopéramide (pharmacologie), Réplication virale (), Tests de criblage à haut débit, Virus du SRAS (), Virus du SRAS (physiologie).
MESH :
- anatomopathologie : Hépatocytes.
- pharmacologie : Antiviraux, Bibliothèques de petites molécules, Chloroquine, Chlorpromazine, Lopinavir, Lopéramide.
- physiologie : Coronavirus du syndrome respiratoire du Moyen-Orient, Coronavirus humain 229E, Virus du SRAS.
- virologie : Hépatocytes.
Pascal (Inist)
- Agrément de médicaments, Animaux, Cellules Vero, Concentration inhibitrice 50, Coronavirus du syndrome respiratoire du Moyen-Orient, Coronavirus humain 229E, Criblage, Dépistage, Food and Drug Administration, Bibliothèque, Humains, Hépatocytes, Identification, Lignée cellulaire, Molécule petite, Inhibiteur, Coronavirus, Réplication, In vitro, Culture cellulaire, Réplication virale, Syndrome respiratoire du Moyen-Orient, Tests de criblage à haut débit, Virus du SRAS.
Wicri :
- topic : Bibliothèque.

English descriptors

KwdEn :
- Animals, Antiviral Agents (pharmacology), Cell Line, Cell culture, Chlorocebus aethiops, Chloroquine (pharmacology), Chlorpromazine (pharmacology), Coronavirus, Coronavirus 229E, Human (drug effects), Coronavirus 229E, Human (physiology), Drug Approval, Food and Drug Administration, Hepatocytes (drug effects), Hepatocytes (pathology), Hepatocytes (virology), High-Throughput Screening Assays, Humans, Identification, In vitro, Inhibitor, Inhibitory Concentration 50, Library, Loperamide (pharmacology), Lopinavir (pharmacology), Medical screening, Middle East Respiratory Syndrome Coronavirus (drug effects), Middle East Respiratory Syndrome Coronavirus (physiology), Middle East respiratory syndrome, Replication, SARS Virus (drug effects), SARS Virus (physiology), Screening, Small Molecule Libraries (pharmacology), Small molecule, 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 [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:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4136071

Affiliations:

Le document en format XML

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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term>
<term>Antiviral Agents (pharmacology)</term>
<term>Cell Line</term>
<term>Cell culture</term>
<term>Chlorocebus aethiops</term>
<term>Chloroquine (pharmacology)</term>
<term>Chlorpromazine (pharmacology)</term>
<term>Coronavirus</term>
<term>Coronavirus 229E, Human (drug effects)</term>
<term>Coronavirus 229E, Human (physiology)</term>
<term>Drug Approval</term>
<term>Food and Drug Administration</term>
<term>Hepatocytes (drug effects)</term>
<term>Hepatocytes (pathology)</term>
<term>Hepatocytes (virology)</term>
<term>High-Throughput Screening Assays</term>
<term>Humans</term>
<term>Identification</term>
<term>In vitro</term>
<term>Inhibitor</term>
<term>Inhibitory Concentration 50</term>
<term>Library</term>
<term>Loperamide (pharmacology)</term>
<term>Lopinavir (pharmacology)</term>
<term>Medical screening</term>
<term>Middle East Respiratory Syndrome Coronavirus (drug effects)</term>
<term>Middle East Respiratory Syndrome Coronavirus (physiology)</term>
<term>Middle East respiratory syndrome</term>
<term>Replication</term>
<term>SARS Virus (drug effects)</term>
<term>SARS Virus (physiology)</term>
<term>Screening</term>
<term>Small Molecule Libraries (pharmacology)</term>
<term>Small molecule</term>
<term>Vero Cells</term>
<term>Virus Replication (drug effects)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Agrément de médicaments</term>
<term>Animaux</term>
<term>Antiviraux (pharmacologie)</term>
<term>Bibliothèques de petites molécules (pharmacologie)</term>
<term>Cellules Vero</term>
<term>Chloroquine (pharmacologie)</term>
<term>Chlorpromazine (pharmacologie)</term>
<term>Concentration inhibitrice 50</term>
<term>Coronavirus du syndrome respiratoire du Moyen-Orient ()</term>
<term>Coronavirus du syndrome respiratoire du Moyen-Orient (physiologie)</term>
<term>Coronavirus humain 229E ()</term>
<term>Coronavirus humain 229E (physiologie)</term>
<term>Humains</term>
<term>Hépatocytes ()</term>
<term>Hépatocytes (anatomopathologie)</term>
<term>Hépatocytes (virologie)</term>
<term>Lignée cellulaire</term>
<term>Lopinavir (pharmacologie)</term>
<term>Lopéramide (pharmacologie)</term>
<term>Réplication virale ()</term>
<term>Tests de criblage à haut débit</term>
<term>Virus du SRAS ()</term>
<term>Virus du SRAS (physiologie)</term>
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<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="anatomopathologie" xml:lang="fr"><term>Hépatocytes</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="pharmacologie" xml:lang="fr"><term>Antiviraux</term>
<term>Bibliothèques de petites molécules</term>
<term>Chloroquine</term>
<term>Chlorpromazine</term>
<term>Lopinavir</term>
<term>Lopéramide</term>
</keywords>
<keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term>
<term>Coronavirus humain 229E</term>
<term>Virus du SRAS</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="virologie" xml:lang="fr"><term>Hépatocytes</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>
<keywords scheme="Pascal" xml:lang="fr"><term>Agrément de médicaments</term>
<term>Animaux</term>
<term>Cellules Vero</term>
<term>Concentration inhibitrice 50</term>
<term>Coronavirus du syndrome respiratoire du Moyen-Orient</term>
<term>Coronavirus humain 229E</term>
<term>Criblage</term>
<term>Dépistage</term>
<term>Food and Drug Administration</term>
<term>Bibliothèque</term>
<term>Humains</term>
<term>Hépatocytes</term>
<term>Identification</term>
<term>Lignée cellulaire</term>
<term>Molécule petite</term>
<term>Inhibiteur</term>
<term>Coronavirus</term>
<term>Réplication</term>
<term>In vitro</term>
<term>Culture cellulaire</term>
<term>Réplication virale</term>
<term>Syndrome respiratoire du Moyen-Orient</term>
<term>Tests de criblage à haut débit</term>
<term>Virus du SRAS</term>
</keywords>
<keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Bibliothèque</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<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.</div>
</front>
</TEI>
<affiliations><list><country><li>Belgique</li>
<li>Pays-Bas</li>
</country>
<region><li>Hollande-Méridionale</li>
</region>
<settlement><li>Leyde</li>
<li>Rotterdam</li>
</settlement>
</list>
<tree><country name="Pays-Bas"><region name="Hollande-Méridionale"><name sortKey="De Wilde, Adriaan H" sort="De Wilde, Adriaan H" uniqKey="De Wilde A" first="Adriaan H." last="De Wilde">Adriaan H. De Wilde</name>
</region>
<name sortKey="Bestebroer, Theo M" sort="Bestebroer, Theo M" uniqKey="Bestebroer T" first="Theo M." last="Bestebroer">Theo M. Bestebroer</name>
<name sortKey="Posthuma, Clara C" sort="Posthuma, Clara C" uniqKey="Posthuma C" first="Clara C." last="Posthuma">Clara C. Posthuma</name>
<name sortKey="Snijder, Eric J" sort="Snijder, Eric J" uniqKey="Snijder E" first="Eric J." last="Snijder">Eric J. Snijder</name>
<name sortKey="Van Den Hoogen, Bernadette G" sort="Van Den Hoogen, Bernadette G" uniqKey="Van Den Hoogen B" first="Bernadette G." last="Van Den Hoogen">Bernadette G. Van Den Hoogen</name>
<name sortKey="Van Nieuwkoop, Stefan" sort="Van Nieuwkoop, Stefan" uniqKey="Van Nieuwkoop S" first="Stefan" last="Van Nieuwkoop">Stefan Van Nieuwkoop</name>
<name sortKey="Zevenhoven Dobbe, Jessika C" sort="Zevenhoven Dobbe, Jessika C" uniqKey="Zevenhoven Dobbe J" first="Jessika C." last="Zevenhoven-Dobbe">Jessika C. Zevenhoven-Dobbe</name>
</country>
<country name="Belgique"><noRegion><name sortKey="Jochmans, Dirk" sort="Jochmans, Dirk" uniqKey="Jochmans D" first="Dirk" last="Jochmans">Dirk Jochmans</name>
</noRegion>
<name sortKey="Neyts, Johan" sort="Neyts, Johan" uniqKey="Neyts J" first="Johan" last="Neyts">Johan Neyts</name>
</country>
</tree>
</affiliations>
</record>

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Screening of an FDA-Approved Compound Library Identifies Four Small-Molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Replication in Cell Culture

Screening of an FDA-Approved Compound Library Identifies Four Small-Molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Replication in Cell Culture

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