Institute of Human Virology, Zhongshan School of Medicine, and Key Laboratory of Tropical Disease Control of Ministry of Education, Sun Yat-sen University, Guangzhou, 510080, China; NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100176, China.
State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China.
Antiviral Res. 2021 Dec;196:105210. doi: 10.1016/j.antiviral.2021.105210. Epub 2021 Nov 19.
Zika virus (ZIKV) infection could lead to Guillain-Barré syndrome in adults and microcephaly in the newborns from infected pregnant women. To date, there is no specific drug for the treatment of ZIKV infection. In this study, we sought to screen inhibitors against ZIKV infection from a natural product library. A ZIKV replicon was used to screen a library containing 1680 natural compounds. We explored the antiviral mechanism of the compound candidate in vitro and in vivo infection models. Ascomycin, a macrolide from Streptomyces hygroscopicus, was identified with inhibitory effect against ZIKV in Vero cells (IC = 0.11 μM), hepatoma cell Huh7 (IC = 0.38 μM), and glioblastoma cell SNB-19 (IC = 0.06 μM), far below the cytotoxic concentrations. Mechanistic study revealed that Ascomycin suppressed ZIKV RNA replication step during the life cycle and the regulation of calcineurin-NFAT pathway maybe involved in this inhibitory effect, independent of innate immunity activation. Moreover, we found that Ascomycin also inhibited the infection of other Flaviviridae members, such as hepatitis C virus and dengue virus. Ascomycin reduced ZIKV load in blood by up to 3500-fold in A129 mice. Meanwhile, the infection in the mice brain was undetectable by immunohistochemistry staining. Together, these findings reveal a critical role of Ascomycin in the inhibition of ZIKV and related viruses, facilitating the development of novel antiviral agents.
寨卡病毒（ZIKV）感染可导致成人格林-巴利综合征和感染孕妇的新生儿小头畸形。迄今为止，尚无针对 ZIKV 感染的特效药物。在本研究中，我们试图从天然产物库中筛选针对 ZIKV 感染的抑制剂。使用 ZIKV 复制子筛选包含 1680 种天然化合物的文库。我们在体外和体内感染模型中探讨了候选化合物的抗病毒机制。从吸水链霉菌中分离得到的大环内酯类抗生素 Aspergillomarasmine 对 ZIKV 在 Vero 细胞（IC = 0.11 μM）、肝癌细胞 Huh7（IC = 0.38 μM）和神经胶质瘤细胞 SNB-19（IC = 0.06 μM）中的感染具有抑制作用，其半数抑制浓度（IC50）远低于细胞毒性浓度。机制研究表明，Aspergillomarasmine 抑制 ZIKV 生命周期中的 RNA 复制步骤，而钙调神经磷酸酶-NFAT 通路的调节可能参与了这种抑制作用，与先天免疫激活无关。此外，我们发现 Aspergillomarasmine 还抑制其他黄病毒科成员的感染，如丙型肝炎病毒和登革热病毒。Aspergillomarasmine 可使 A129 小鼠体内的 ZIKV 载量减少高达 3500 倍。同时，免疫组织化学染色显示小鼠脑组织中的感染无法检测到。综上所述，这些发现揭示了 Aspergillomarasmine 在抑制 ZIKV 和相关病毒方面的关键作用，为开发新型抗病毒药物提供了依据。
