Rausch Keiko, Hackett Brent A, Weinbren Nathan L, Reeder Sophia M, Sadovsky Yoel, Hunter Christopher A, Schultz David C, Coyne Carolyn B, Cherry Sara
Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA 19104, USA; Department of Obstetrics, Gynecology, and Reproductive Science, University of Pittsburgh, Pittsburgh, PA 19104, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 19104, USA.
Cell Rep. 2017 Jan 17;18(3):804-815. doi: 10.1016/j.celrep.2016.12.068.
Zika virus is an emerging arthropod-borne flavivirus for which there are no vaccines or specific therapeutics. We screened a library of 2,000 bioactive compounds for their ability to block Zika virus infection in three distinct cell types with two different strains of Zika virus. Using a microscopy-based assay, we validated 38 drugs that inhibited Zika virus infection, including FDA-approved nucleoside analogs. Cells expressing high levels of the attachment factor AXL can be protected from infection with receptor tyrosine kinase inhibitors, while placental-derived cells that lack AXL expression are insensitive to this inhibition. Importantly, we identified nanchangmycin as a potent inhibitor of Zika virus entry across all cell types tested, including physiologically relevant primary cells. Nanchangmycin also was active against other medically relevant viruses, including West Nile, dengue, and chikungunya viruses that use a similar route of entry. This study provides a resource of small molecules to study Zika virus pathogenesis.
寨卡病毒是一种新出现的节肢动物传播的黄病毒，目前尚无疫苗或特效疗法。我们筛选了一个包含2000种生物活性化合物的文库，检测它们在三种不同细胞类型中阻断两种不同寨卡病毒株感染的能力。通过基于显微镜的检测方法，我们验证了38种抑制寨卡病毒感染的药物，包括美国食品药品监督管理局（FDA）批准的核苷类似物。表达高水平黏附因子AXL的细胞可通过受体酪氨酸激酶抑制剂免受感染，而缺乏AXL表达的胎盘来源细胞对这种抑制不敏感。重要的是，我们确定南昌霉素是在所有测试细胞类型中，包括生理相关原代细胞中寨卡病毒进入的有效抑制剂。南昌霉素对其他医学相关病毒也有活性，包括使用类似进入途径的西尼罗河病毒、登革热病毒和基孔肯雅病毒。本研究提供了用于研究寨卡病毒发病机制的小分子资源。
