Wang Yaxin, Cao Lin, Zhai Yangyang, Ma Jiaming, Nie Quandeng, Li Ting, Yin Zheng, Sun Yuna, Shang Luqing
College of Pharmacy & State Key Laboratory of Medicinal Chemical Biology & Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, China; National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China.
College of Pharmacy & State Key Laboratory of Medicinal Chemical Biology & Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, China.
Antiviral Res. 2017 May;141:91-100. doi: 10.1016/j.antiviral.2017.01.002. Epub 2017 Jan 5.
Enterovirus 71 (EV71) is one of the major etiological agents of human hand-foot-and-mouth disease (HFMD) worldwide. EV71 infection in young children and people with immunodeficiency causes severe symptoms with a high fatality rates. However, there is still no approved drugs to treat such infections. Based on our previous report of a peptide-aldehyde anti-EV71 protease, we present here a highly specific α-hydroxy-nitrile derivative NK-1.9k, which inhibited the proliferation of multiple EV71 strains and coxsackievirus A16 (CVA16) in various cells with EC of 37.0 nM with low cytotoxicity (CC > 200 μM). The hydroxy-nitrile covalent warhead conferred NK-1.9k high potency and selectivity to interact with the cysteine residue of the active site of the viral protease. We also documented the resistance to NK-1.9k with a N69S mutation in EV71 3C. The combination of NK-1.9k and EV71 polymerase or entry inhibitors produced strong synergistic antiviral effects. Collectively, our findings suggest our compounds can potentially be developed as drugs for the treatment of HFMD.
肠道病毒71型（EV71）是全球人类手足口病（HFMD）的主要病原体之一。幼儿和免疫缺陷人群感染EV71会引发严重症状，死亡率很高。然而，目前仍没有获批用于治疗此类感染的药物。基于我们之前关于肽醛类抗EV71蛋白酶的报告，我们在此展示一种高度特异性的α-羟基腈衍生物NK-1.9k，它能抑制多种EV71毒株和柯萨奇病毒A16型（CVA16）在多种细胞中的增殖，半数有效浓度（EC）为37.0 nM，细胞毒性低（半数细胞毒性浓度CC>200 μM）。羟基腈共价弹头赋予NK-1.9k高效力和选择性，使其能与病毒蛋白酶活性位点的半胱氨酸残基相互作用。我们还记录了EV71 3C中N69S突变对NK-1.9k产生的耐药性。NK-1.9k与EV71聚合酶或进入抑制剂联合使用产生了强大的协同抗病毒效果。总体而言，我们的研究结果表明，我们的化合物有潜力被开发为治疗手足口病的药物。
