Screening of an FDA-Approved Compound Library Identifies Four Small-Molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Replication in Cell Culture
Identifieur interne : 000014 ( PascalFrancis/Corpus ); précédent : 000013; suivant : 000015Screening 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.
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- Pascal (Inist)
English descriptors
- KwdEn :
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.
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NO : | PASCAL 14-0220020 INIST |
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ET : | Screening of an FDA-Approved Compound Library Identifies Four Small-Molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Replication in Cell Culture |
AU : | DE WILDE (Adriaan H.); JOCHMANS (Dirk); POSTHUMA (Clara C.); ZEVENHOVEN-DOBBE (Jessika C.); VAN NIEUWKOOP (Stefan); BESTEBROER (Theo M.); VAN DEN HOOGEN (Bernadette G.); NEYTS (Johan); SNIJDER (Eric J.) |
AF : | Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center/Leiden/Pays-Bas (1 aut., 3 aut., 4 aut., 9 aut.); Rega Institute for Medical Research, KU/Leuven/Belgique (2 aut., 8 aut.); Department of Viroscience, Erasmus Medical Center/Rotterdam/Pays-Bas (5 aut., 6 aut., 7 aut.) |
DT : | Publication en série; Niveau analytique |
SO : | Antimicrobial agents and chemotherapy; ISSN 0066-4804; Coden AACHAX; Etats-Unis; Da. 2014; Vol. 58; No. 8; Pp. 4875-4884; Bibl. 85 ref. |
LA : | Anglais |
EA : | 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. |
CC : | 002B02S; 002B05C02C |
FD : | Criblage; Dépistage; Food and Drug Administration; Bibliothèque; Identification; Molécule petite; Inhibiteur; Coronavirus; Réplication; In vitro; Culture cellulaire; Syndrome respiratoire du Moyen-Orient |
FG : | Coronaviridae; Nidovirales; Virus; Pathologie de l'appareil respiratoire; Virose; Infection |
ED : | Screening; Medical screening; Food and Drug Administration; Library; Identification; Small molecule; Inhibitor; Coronavirus; Replication; In vitro; Cell culture; Middle East respiratory syndrome |
EG : | Coronaviridae; Nidovirales; Virus; Respiratory disease; Viral disease; Infection |
SD : | Cernido; Descubrimiento; Food and Drug Administration; Biblioteca; Identificación; Molécula pequeña; Inhibidor; Coronavirus; Replicación; In vitro; Cultivo celular |
LO : | INIST-13334.354000504837190730 |
ID : | 14-0220020 |
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<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>
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</fC03>
<fC03 i1="04" i2="X" l="ENG"><s0>Library</s0>
<s5>04</s5>
</fC03>
<fC03 i1="04" i2="X" l="SPA"><s0>Biblioteca</s0>
<s5>04</s5>
</fC03>
<fC03 i1="05" i2="X" l="FRE"><s0>Identification</s0>
<s5>05</s5>
</fC03>
<fC03 i1="05" i2="X" l="ENG"><s0>Identification</s0>
<s5>05</s5>
</fC03>
<fC03 i1="05" i2="X" l="SPA"><s0>Identificación</s0>
<s5>05</s5>
</fC03>
<fC03 i1="06" i2="X" l="FRE"><s0>Molécule petite</s0>
<s5>06</s5>
</fC03>
<fC03 i1="06" i2="X" l="ENG"><s0>Small molecule</s0>
<s5>06</s5>
</fC03>
<fC03 i1="06" i2="X" l="SPA"><s0>Molécula pequeña</s0>
<s5>06</s5>
</fC03>
<fC03 i1="07" i2="X" l="FRE"><s0>Inhibiteur</s0>
<s5>07</s5>
</fC03>
<fC03 i1="07" i2="X" l="ENG"><s0>Inhibitor</s0>
<s5>07</s5>
</fC03>
<fC03 i1="07" i2="X" l="SPA"><s0>Inhibidor</s0>
<s5>07</s5>
</fC03>
<fC03 i1="08" i2="X" l="FRE"><s0>Coronavirus</s0>
<s2>NW</s2>
<s5>08</s5>
</fC03>
<fC03 i1="08" i2="X" l="ENG"><s0>Coronavirus</s0>
<s2>NW</s2>
<s5>08</s5>
</fC03>
<fC03 i1="08" i2="X" l="SPA"><s0>Coronavirus</s0>
<s2>NW</s2>
<s5>08</s5>
</fC03>
<fC03 i1="09" i2="X" l="FRE"><s0>Réplication</s0>
<s5>09</s5>
</fC03>
<fC03 i1="09" i2="X" l="ENG"><s0>Replication</s0>
<s5>09</s5>
</fC03>
<fC03 i1="09" i2="X" l="SPA"><s0>Replicación</s0>
<s5>09</s5>
</fC03>
<fC03 i1="10" i2="X" l="FRE"><s0>In vitro</s0>
<s5>10</s5>
</fC03>
<fC03 i1="10" i2="X" l="ENG"><s0>In vitro</s0>
<s5>10</s5>
</fC03>
<fC03 i1="10" i2="X" l="SPA"><s0>In vitro</s0>
<s5>10</s5>
</fC03>
<fC03 i1="11" i2="X" l="FRE"><s0>Culture cellulaire</s0>
<s5>11</s5>
</fC03>
<fC03 i1="11" i2="X" l="ENG"><s0>Cell culture</s0>
<s5>11</s5>
</fC03>
<fC03 i1="11" i2="X" l="SPA"><s0>Cultivo celular</s0>
<s5>11</s5>
</fC03>
<fC03 i1="12" i2="X" l="FRE"><s0>Syndrome respiratoire du Moyen-Orient</s0>
<s4>CD</s4>
<s5>96</s5>
</fC03>
<fC03 i1="12" i2="X" l="ENG"><s0>Middle East respiratory syndrome</s0>
<s4>CD</s4>
<s5>96</s5>
</fC03>
<fC07 i1="01" i2="X" l="FRE"><s0>Coronaviridae</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="01" i2="X" l="ENG"><s0>Coronaviridae</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="01" i2="X" l="SPA"><s0>Coronaviridae</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="02" i2="X" l="FRE"><s0>Nidovirales</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="02" i2="X" l="ENG"><s0>Nidovirales</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="02" i2="X" l="SPA"><s0>Nidovirales</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="03" i2="X" l="FRE"><s0>Virus</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="03" i2="X" l="ENG"><s0>Virus</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="03" i2="X" l="SPA"><s0>Virus</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="04" i2="X" l="FRE"><s0>Pathologie de l'appareil respiratoire</s0>
<s5>37</s5>
</fC07>
<fC07 i1="04" i2="X" l="ENG"><s0>Respiratory disease</s0>
<s5>37</s5>
</fC07>
<fC07 i1="04" i2="X" l="SPA"><s0>Aparato respiratorio patología</s0>
<s5>37</s5>
</fC07>
<fC07 i1="05" i2="X" l="FRE"><s0>Virose</s0>
<s5>38</s5>
</fC07>
<fC07 i1="05" i2="X" l="ENG"><s0>Viral disease</s0>
<s5>38</s5>
</fC07>
<fC07 i1="05" i2="X" l="SPA"><s0>Virosis</s0>
<s5>38</s5>
</fC07>
<fC07 i1="06" i2="X" l="FRE"><s0>Infection</s0>
</fC07>
<fC07 i1="06" i2="X" l="ENG"><s0>Infection</s0>
</fC07>
<fC07 i1="06" i2="X" l="SPA"><s0>Infección</s0>
</fC07>
<fN21><s1>265</s1>
</fN21>
<fN44 i1="01"><s1>OTO</s1>
</fN44>
<fN82><s1>OTO</s1>
</fN82>
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<server><NO>PASCAL 14-0220020 INIST</NO>
<ET>Screening of an FDA-Approved Compound Library Identifies Four Small-Molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Replication in Cell Culture</ET>
<AU>DE WILDE (Adriaan H.); JOCHMANS (Dirk); POSTHUMA (Clara C.); ZEVENHOVEN-DOBBE (Jessika C.); VAN NIEUWKOOP (Stefan); BESTEBROER (Theo M.); VAN DEN HOOGEN (Bernadette G.); NEYTS (Johan); SNIJDER (Eric J.)</AU>
<AF>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center/Leiden/Pays-Bas (1 aut., 3 aut., 4 aut., 9 aut.); Rega Institute for Medical Research, KU/Leuven/Belgique (2 aut., 8 aut.); Department of Viroscience, Erasmus Medical Center/Rotterdam/Pays-Bas (5 aut., 6 aut., 7 aut.)</AF>
<DT>Publication en série; Niveau analytique</DT>
<SO>Antimicrobial agents and chemotherapy; ISSN 0066-4804; Coden AACHAX; Etats-Unis; Da. 2014; Vol. 58; No. 8; Pp. 4875-4884; Bibl. 85 ref.</SO>
<LA>Anglais</LA>
<EA>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.</EA>
<CC>002B02S; 002B05C02C</CC>
<FD>Criblage; Dépistage; Food and Drug Administration; Bibliothèque; Identification; Molécule petite; Inhibiteur; Coronavirus; Réplication; In vitro; Culture cellulaire; Syndrome respiratoire du Moyen-Orient</FD>
<FG>Coronaviridae; Nidovirales; Virus; Pathologie de l'appareil respiratoire; Virose; Infection</FG>
<ED>Screening; Medical screening; Food and Drug Administration; Library; Identification; Small molecule; Inhibitor; Coronavirus; Replication; In vitro; Cell culture; Middle East respiratory syndrome</ED>
<EG>Coronaviridae; Nidovirales; Virus; Respiratory disease; Viral disease; Infection</EG>
<SD>Cernido; Descubrimiento; Food and Drug Administration; Biblioteca; Identificación; Molécula pequeña; Inhibidor; Coronavirus; Replicación; In vitro; Cultivo celular</SD>
<LO>INIST-13334.354000504837190730</LO>
<ID>14-0220020</ID>
</server>
</inist>
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