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

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

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 EC(50) 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 EC(50) of each drug by 1–3 times. CONCLUSIONS: Interferon-β1b with mycophenolic acid should be considered in treatment trials of MERS.