PDF(Pubmed)
Abstract：
Foot-and-mouth disease (FMD) is a highly contagious disease in cloven-hoofed animals, caused by the foot-and-mouth disease virus (FMDV). It is endemic in Asia and Africa but spreads sporadically throughout the world, resulting in significant losses in the livestock industry. Effective anti-FMDV therapeutics could be a supportive control strategy. Herein, we utilized computer-aided, structure-based virtual screening to filter lead compounds from the National Cancer Institute (NCI) diversity and mechanical libraries using FMDV 3C protease (3Cpro) as the target. Seven hit compounds were further examined via cell-based antiviral and intracellular protease assays, in which two compounds (NSC116640 and NSC332670) strongly inhibited FMDV, with EC50 values at the micromolar level of 2.88 µM (SI = 73.15) and 5.92 µM (SI = 11.11), respectively. These compounds could inactivate extracellular virus directly in a virucidal assay by reducing 1.00 to 2.27 log TCID50 of the viral titers in 0-60 min. In addition, the time-of-addition assay revealed that NSC116640 inhibited FMDV at the early stage of infection (0-8 h), while NSC332670 diminished virus titers when added simultaneously at infection (0 h). Both compounds showed good FMDV 3Cpro inhibition with IC50 values of 10.85 µM (NSC116640) and 4.21 µM (NSC332670). The molecular docking of the compounds on FMDV 3Cpro showed their specific interactions with amino acids in the catalytic triad of FMDV 3Cpro. Both preferentially reacted with enzymes and proteases in physicochemical and ADME analysis studies. The results revealed two novel small molecules with antiviral activities against FMDV and probably related picornaviruses.
摘要：
口蹄疫（FMD）是偶蹄动物的高度传染性疾病，由口蹄疫病毒（FMDV）引起。它在亚洲和非洲流行，但在世界各地零星传播，造成畜牧业的重大损失。有效的抗FMDV疗法可能是支持性控制策略。在这里，我们利用计算机辅助，基于结构的虚拟筛选，以FMDV3C蛋白酶（3Cpro）为靶标，过滤来自美国国家癌症研究所（NCI）多样性和机械库的先导化合物。通过基于细胞的抗病毒和细胞内蛋白酶测定进一步检查了七个命中化合物，其中两个化合物(NSC116640和NSC332670)强烈抑制FMDV，EC50值在微摩尔水平为2.88µM（SI=73.15）和5.92µM（SI=11.11），分别。通过在0-60分钟内将病毒滴度的1.00降低至2.27logTCID50,这些化合物可以在杀病毒测定中直接灭活细胞外病毒。此外,添加时间测定显示NSC116640在感染早期（0-8小时）抑制FMDV，而NSC332670在感染时(0小时)同时添加时降低了病毒滴度。两种化合物均显示出良好的FMDV3Cpro抑制作用，IC50值为10.85µM（NSC116640）和4.21µM（NSC332670）。化合物在FMDV3Cpro上的分子对接显示了它们与FMDV3Cpro催化三联体中氨基酸的特异性相互作用。在物理化学和ADME分析研究中，两者都优先与酶和蛋白酶反应。结果揭示了两种新的小分子对FMDV和可能相关的小核糖核酸病毒具有抗病毒活性。
