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J Infect. Broad-Spectrum Antivirals For The Emerging Middle East Respiratory Syndrome Coronavirus
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Journal of Infection, Available online 3 October 2013. In Press, Accepted Manuscript
Broad-Spectrum Antivirals For The Emerging Middle East Respiratory Syndrome Coronavirus
Jasper F.W. Chan a, b, c, 1, Kwok-**** Chan b, 1, Richard Y.T. Kao a, b, c, 1, Kelvin K.W. To a, b, c, Bo-Jian Zheng a, b, c, Clara P.Y. Li b, Patrick T.W. Li b, Jun Dai b, Florence K.Y. Mok b, Honglin Chen a, b, c, Frederick G. Hayden d, Kwok-Yung Yuen a, b, c.
a State Key Laboratory of Emerging Infectious Diseases, the University of Hong Kong, Hong Kong Special Administrative Region, China; b Department of Microbiology, and the University of Hong Kong, Hong Kong Special Administrative Region, China; c Research Centre of Infection and Immunology, the University of Hong Kong, Hong Kong Special Administrative Region, China; and d Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA
Summary
Objectives
Middle East respiratory syndrome coronavirus (MERS-CoV) has emerged to cause fatal infections in patients in the Middle East and traveler-associated secondary cases in Europe and Africa. Person-to-person transmission is evident in outbreaks involving household and hospital contacts. Effective antivirals are urgently needed.
Methods
We used small compound-based forward chemical genetics to screen a chemical library of 1280 known drugs against influenza A virus in Biosafety Level-2 laboratory. We then assessed the anti-MERS-CoV activities of the identified compounds and of interferons, nelfinavir, lopinavir, and nitazoxanide because of their reported anti-coronavirus activities in cytopathic effect inhibition, viral yield reduction, and plaque reduction assays.
Results
Ten compounds were identified as primary hits in high-throughput screening. Only mycophenolic acid exhibited low EC50 and high selectivity index. Additionally, ribavirin and interferons also exhibited in-vitro anti-MERS-CoV activity. The serum concentrations achievable at therapeutic doses of mycophenolic acid and interferon-β1b were 60-300 and 3-4 times higher than the concentrations at which in-vitro anti-MERS-CoV activities were demonstrated, whereas that of ribavirin was ∼2 times lower. Combination of mycophenolic acid and interferon-β1b lowered the EC50 of each drug by 1-3 times.
Conclusions
Interferon-β1b with mycophenolic acid should be considered in treatment trials of MERS.
Keywords: coronavirus; Middle East; mycophenolic acid; interferon; ribavirin; antiviral
Corresponding author. Mailing address: Carol Yu Centre for Infection, Department of Microbiology, The University of Hong Kong, Queen Mary Hospital, 102, Pokfulam Road, Pokfulam, Hong Kong Special Administrative Region, China. Tel.: +86 852 22554892; fax: +86 852 28551241.1
The authors contributed equally to the manuscript.
Copyright ? 2013 Published by Elsevier Ltd.
Copyright ? 2013 Elsevier B.V. All rights reserved. ScienceDirect? is a registered trademark of Elsevier B.V.
http://dx.doi.org/10.1016/j.jinf.2013.09.029
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Journal of Infection, Available online 3 October 2013. In Press, Accepted Manuscript
Broad-Spectrum Antivirals For The Emerging Middle East Respiratory Syndrome Coronavirus
Jasper F.W. Chan a, b, c, 1, Kwok-**** Chan b, 1, Richard Y.T. Kao a, b, c, 1, Kelvin K.W. To a, b, c, Bo-Jian Zheng a, b, c, Clara P.Y. Li b, Patrick T.W. Li b, Jun Dai b, Florence K.Y. Mok b, Honglin Chen a, b, c, Frederick G. Hayden d, Kwok-Yung Yuen a, b, c.
a State Key Laboratory of Emerging Infectious Diseases, the University of Hong Kong, Hong Kong Special Administrative Region, China; b Department of Microbiology, and the University of Hong Kong, Hong Kong Special Administrative Region, China; c Research Centre of Infection and Immunology, the University of Hong Kong, Hong Kong Special Administrative Region, China; and d Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA
Summary
Objectives
Middle East respiratory syndrome coronavirus (MERS-CoV) has emerged to cause fatal infections in patients in the Middle East and traveler-associated secondary cases in Europe and Africa. Person-to-person transmission is evident in outbreaks involving household and hospital contacts. Effective antivirals are urgently needed.
Methods
We used small compound-based forward chemical genetics to screen a chemical library of 1280 known drugs against influenza A virus in Biosafety Level-2 laboratory. We then assessed the anti-MERS-CoV activities of the identified compounds and of interferons, nelfinavir, lopinavir, and nitazoxanide because of their reported anti-coronavirus activities in cytopathic effect inhibition, viral yield reduction, and plaque reduction assays.
Results
Ten compounds were identified as primary hits in high-throughput screening. Only mycophenolic acid exhibited low EC50 and high selectivity index. Additionally, ribavirin and interferons also exhibited in-vitro anti-MERS-CoV activity. The serum concentrations achievable at therapeutic doses of mycophenolic acid and interferon-β1b were 60-300 and 3-4 times higher than the concentrations at which in-vitro anti-MERS-CoV activities were demonstrated, whereas that of ribavirin was ∼2 times lower. Combination of mycophenolic acid and interferon-β1b lowered the EC50 of each drug by 1-3 times.
Conclusions
Interferon-β1b with mycophenolic acid should be considered in treatment trials of MERS.
Keywords: coronavirus; Middle East; mycophenolic acid; interferon; ribavirin; antiviral
Corresponding author. Mailing address: Carol Yu Centre for Infection, Department of Microbiology, The University of Hong Kong, Queen Mary Hospital, 102, Pokfulam Road, Pokfulam, Hong Kong Special Administrative Region, China. Tel.: +86 852 22554892; fax: +86 852 28551241.1
The authors contributed equally to the manuscript.
Copyright ? 2013 Published by Elsevier Ltd.
Copyright ? 2013 Elsevier B.V. All rights reserved. ScienceDirect? is a registered trademark of Elsevier B.V.
http://dx.doi.org/10.1016/j.jinf.2013.09.029
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