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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.
Antimicrob Agents Chemother. 2014 Aug; 58(8):4875-84.AA

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.

Authors+Show Affiliations

Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, Netherlands.Rega Institute for Medical Research, KU, Leuven, Belgium.Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, Netherlands.Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, Netherlands.Department of Viroscience, Erasmus Medical Center, Rotterdam, Netherlands.Department of Viroscience, Erasmus Medical Center, Rotterdam, Netherlands.Department of Viroscience, Erasmus Medical Center, Rotterdam, Netherlands.Rega Institute for Medical Research, KU, Leuven, Belgium Johan.Neyts@rega.kuleuven.be E.J.Snijder@LUMC.nl.Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, Netherlands Johan.Neyts@rega.kuleuven.be E.J.Snijder@LUMC.nl.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24841269

Citation

de Wilde, Adriaan H., et al. "Screening of an FDA-approved Compound Library Identifies Four Small-molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Replication in Cell Culture." Antimicrobial Agents and Chemotherapy, vol. 58, no. 8, 2014, pp. 4875-84.
de Wilde AH, Jochmans D, Posthuma CC, et al. Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob Agents Chemother. 2014;58(8):4875-84.
de Wilde, A. H., Jochmans, D., Posthuma, C. C., Zevenhoven-Dobbe, J. C., van Nieuwkoop, S., Bestebroer, T. M., van den Hoogen, B. G., Neyts, J., & Snijder, E. J. (2014). Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrobial Agents and Chemotherapy, 58(8), 4875-84. https://doi.org/10.1128/AAC.03011-14
de Wilde AH, et al. Screening of an FDA-approved Compound Library Identifies Four Small-molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Replication in Cell Culture. Antimicrob Agents Chemother. 2014;58(8):4875-84. PubMed PMID: 24841269.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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, AU - Jochmans,Dirk, AU - Posthuma,Clara C, AU - Zevenhoven-Dobbe,Jessika C, AU - van Nieuwkoop,Stefan, AU - Bestebroer,Theo M, AU - van den Hoogen,Bernadette G, AU - Neyts,Johan, AU - Snijder,Eric J, Y1 - 2014/05/19/ PY - 2014/5/21/entrez PY - 2014/5/21/pubmed PY - 2015/9/15/medline SP - 4875 EP - 84 JF - Antimicrobial agents and chemotherapy JO - Antimicrob. Agents Chemother. VL - 58 IS - 8 N2 - 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. SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/24841269/Screening_of_an_FDA_approved_compound_library_identifies_four_small_molecule_inhibitors_of_Middle_East_respiratory_syndrome_coronavirus_replication_in_cell_culture_ L2 - http://aac.asm.org/cgi/pmidlookup?view=long&pmid=24841269 DB - PRIME DP - Unbound Medicine ER -