State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China; Department of Microbiology, The University of Hong Kong, Hong Kong, China; Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong, China.
J Infect. 2013 Dec;67(6):606-16. doi: 10.1016/j.jinf.2013.09.029. Epub 2013 Oct 3.
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.
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.
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.
Interferon-β1b with mycophenolic acid should be considered in treatment trials of MERS.
中东呼吸综合征冠状病毒（MERS-CoV）已在中东地区导致患者致命感染，并在欧洲和非洲导致旅行者相关的继发性病例。人际传播在涉及家庭和医院接触者的暴发中显而易见。迫切需要有效的抗病毒药物。
我们使用基于小分子的正向化学遗传学方法，在二级生物安全实验室中筛选了针对甲型流感病毒的 1280 种已知药物的化学文库。然后，我们评估了鉴定化合物以及干扰素、奈非那韦和洛匹那韦的抗 MERS-CoV 活性，因为它们在三级生物安全实验室中的细胞病变效应抑制、病毒产量减少和蚀斑减少测定中具有抗冠状病毒活性。
在高通量筛选中确定了 10 种化合物作为主要命中物。只有霉酚酸表现出低 EC50 和高选择性指数。此外，利巴韦林和干扰素也表现出体外抗 MERS-CoV 活性。在治疗剂量下霉酚酸和干扰素-β1b 可达到的血清浓度分别比体外抗 MERS-CoV 活性的浓度高 60-300 倍和 3-4 倍，而利巴韦林的浓度约低 2 倍。霉酚酸和干扰素-β1b 的联合使用使每种药物的 EC50 降低了 1-3 倍。
在 MERS 的治疗试验中，应考虑使用干扰素-β1b 联合霉酚酸。
