Kuivanen Suvi, Bespalov Maxim M, Nandania Jatin, Ianevski Aleksandr, Velagapudi Vidya, De Brabander Jef K, Kainov Denis E, Vapalahti Olli
Department of Virology, Medicum, University of Helsinki, Finland.
Department of Molecular Neurology, Biomedicum Stem Cells Center Research Program Unit, University of Helsinki, Finland.
Antiviral Res. 2017 Mar;139:117-128. doi: 10.1016/j.antiviral.2016.12.022. Epub 2016 Dec 31.
An epidemic of Zika virus (ZIKV) infection associated with congenital abnormalities such as microcephaly, is ongoing in the Americas and the Pacific. Currently there are no approved therapies to treat this emerging viral disease. Here, we tested three cell-directed broad-spectrum antiviral compounds against ZIKV replication using human retinal pigment epithelial (RPE) cells and a low-passage ZIKV strain isolated from fetal brain. We found that obatoclax, SaliPhe, and gemcitabine inhibited ZIKV infections at noncytotoxic concentrations. Moreover, all three compounds prevented production of viral RNA and proteins as well as activation of cellular caspase 8, 3 and 7. However, these compounds differentially affected ZIKV-mediated transcription, translation and posttranslational modifications of cellular factors as well as metabolic pathways indicating that these agents possess different mechanisms of action. Interestingly, combination of obatoclax and SaliPhe at nanomolar concentrations had a synergistic effect against ZIKV infection. Thus, our results provided the foundation for development of broad-spectrum cell-directed antivirals or their combinations for treatment of ZIKV and other emerging viral diseases.
寨卡病毒（ZIKV）感染的疫情在美洲和太平洋地区持续蔓延，该病毒感染与诸如小头畸形等先天性异常有关。目前尚无获批用于治疗这种新出现的病毒性疾病的疗法。在此，我们使用人视网膜色素上皮（RPE）细胞和从胎儿大脑分离出的低代次寨卡病毒毒株，测试了三种细胞导向的广谱抗病毒化合物对寨卡病毒复制的作用。我们发现，obatoclax、SaliPhe和吉西他滨在无细胞毒性的浓度下可抑制寨卡病毒感染。此外，这三种化合物均能阻止病毒RNA和蛋白质的产生以及细胞半胱天冬酶8、3和7的激活。然而，这些化合物对寨卡病毒介导的细胞因子转录、翻译和翻译后修饰以及代谢途径有不同影响，表明这些药物具有不同的作用机制。有趣的是，纳摩尔浓度的obatoclax和SaliPhe联合使用对寨卡病毒感染具有协同作用。因此，我们的研究结果为开发用于治疗寨卡病毒及其他新出现病毒性疾病的广谱细胞导向抗病毒药物或其组合奠定了基础。
