Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus

• Published in: The Journal of infection Vol. 67; no. 6; pp. 606 - 616
• Main Authors: Chan, Jasper F.W, Chan, Kwok-Hung, Kao, Richard Y.T, To, Kelvin K.W, Zheng, Bo-Jian, Li, Clara P.Y, Li, Patrick T.W, Dai, Jun, Mok, Florence K.Y, Chen, Honglin, Hayden, Frederick G, Yuen, Kwok-Yung
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.12.2013; Elsevier; The British Infection Association. Published by Elsevier Ltd
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral; Antiviral agents; Antiviral Agents - pharmacology; Biological and medical sciences; Chlorocebus aethiops; Communicable Diseases, Emerging - drug therapy; Communicable Diseases, Emerging - virology; Coronavirus; Coronavirus - drug effects; Coronavirus Infections - drug therapy; Coronavirus Infections - virology; Disease Outbreaks; Drug Discovery - methods; General aspects; High-Throughput Screening Assays - methods; Human viral diseases; Humans; Infectious Disease; Infectious diseases; Interferon; Interferons - pharmacology; Medical sciences; Middle East; Mycophenolic acid; Mycophenolic Acid - pharmacology; Pharmacology. Drug treatments; Ribavirin; Ribavirin - pharmacology; Vero Cells; Viral diseases; Viral diseases of the respiratory system and ent viral diseases; Viral Load - drug effects; Viral Plaque Assay; Middle East; Antiviral; Interferon; Coronavirus; Mycophenolic acid; Ribavirin; Virus; Infection; Respiratory disease; Viral disease; Coronaviridae; Middle East respiratory syndrome; Nidovirales
• ISSN: 0163-4453; 1532-2742
• DOI: 10.1016/j.jinf.2013.09.029

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, and lopinavir because of their reported anti-coronavirus activities in terms of cytopathic effect inhibition, viral yield reduction, and plaque reduction assays in Biosafety Level-3 laboratory. 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.