Jiangsu Key Laboratory of Preventive Veterinary Medicine, Yangzhou University, Yangzhou, China.
PLoS One. 2012;7(8):e43341. doi: 10.1371/journal.pone.0043341. Epub 2012 Aug 15.
Bluetongue virus (BTV), a member in the family Reoviridae, is a re-emerging animal disease infecting cattle and sheep. With its recent outbreaks in Europe, there is a pressing need for efficacious antivirals. We presented here the identification and characterization of a novel virostatic molecule against BTV, an aminothiophenecarboxylic acid derivative named compound 003 (C003). The virostatic efficacy of C003 could be improved via chemical modification, leading to a de novo synthesized compound 052 (C052). The 50% effective concentrations (EC(50)) of C003 and C052 were determined at 1.76 ± 0.73 µM and 0.27 ± 0.12 µM, respectively. The 50% cytotoxicity concentration (CC(50)) of C003 was over 100 µM and the CC(50) of C052 was at 82.69 µM. Accordingly, the 50% selective index (SI(50)) of C003 and C052 against BTV was over 57 and 306, respectively. The inhibitory effect of C003/C052 on BTV-induced apoptosis was also confirmed via the inhibition of caspase-3/-7 activation post BTV infection. C003/C052 could inhibit BTV induced CPE even when added as late as 24 h.p.i., indicating that they might act at late stage of viral life-cycle. C003/C052 could reduce over two-logs of both the progeny virus production and the number of genomic viral RNA copies. Interestingly, both the activation of host autophagy and viral protein expression were inhibited post BTV infection when cells were treated with C003 and C052, suggesting that C003/C052 might act as virostatic agents via inhibiting host autophagy activation. Although further investigations might be needed to pin down the exact mechanism of C003/C052, our finding suggested that these compounds might be potent lead compounds with potential novel mechanism of action against BTV.
蓝舌病毒（BTV）是呼肠孤病毒科的一个成员，是一种新兴的感染牛和羊的动物疾病。由于其最近在欧洲的爆发，人们迫切需要有效的抗病毒药物。我们在这里介绍了一种针对 BTV 的新型抗病毒化合物的鉴定和特性，它是一种氨基噻吩羧酸衍生物，名为化合物 003（C003）。通过化学修饰可以提高 C003 的抗病毒效果，从而合成了一种新的化合物 052（C052）。C003 和 C052 的 50%有效浓度（EC（50））分别为 1.76±0.73µM 和 0.27±0.12µM。C003 的 50%细胞毒性浓度（CC（50））超过 100µM，C052 的 CC（50）为 82.69µM。因此，C003 和 C052 对 BTV 的 50%选择性指数（SI（50））分别超过 57 和 306。通过抑制 BTV 感染后 caspase-3/-7 的激活，也证实了 C003/C052 对 BTV 诱导凋亡的抑制作用。即使在感染后 24 小时添加，C003/C052 也可以抑制 BTV 诱导的 CPE，表明它们可能作用于病毒生命周期的晚期。C003/C052 可以减少两个对数的子代病毒产量和基因组病毒 RNA 拷贝数。有趣的是，当用 C003 和 C052 处理细胞时，BTV 感染后宿主自噬的激活和病毒蛋白的表达都被抑制，这表明 C003/C052 可能通过抑制宿主自噬的激活来发挥抗病毒作用。虽然进一步的研究可能需要确定 C003/C052 的确切机制，但我们的发现表明，这些化合物可能是针对 BTV 的有效先导化合物，具有潜在的新型作用机制。
