Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06511, USA.
Cell Rep. 2017 Dec 12;21(11):3032-3039. doi: 10.1016/j.celrep.2017.11.054.
The mosquito-borne flaviviruses include important human pathogens such as dengue, Zika, West Nile, and yellow fever viruses, which pose a serious threat for global health. Recent genetic screens identified endoplasmic reticulum (ER)-membrane multiprotein complexes, including the oligosaccharyltransferase (OST) complex, as critical flavivirus host factors. Here, we show that a chemical modulator of the OST complex termed NGI-1 has promising antiviral activity against flavivirus infections. We demonstrate that NGI-1 blocks viral RNA replication and that antiviral activity does not depend on inhibition of the N-glycosylation function of the OST. Viral mutants adapted to replicate in cells deficient of the OST complex showed resistance to NGI-1 treatment, reinforcing the on-target activity of NGI-1. Lastly, we show that NGI-1 also has strong antiviral activity in primary and disease-relevant cell types. This study provides an example for advancing from the identification of genetic determinants of infection to a host-directed antiviral compound with broad activity against flaviviruses.
蚊媒黄病毒包括登革热、寨卡、西尼罗河和黄热病等重要的人类病原体，它们对全球健康构成严重威胁。最近的遗传筛选确定了内质网（ER）膜多蛋白复合物，包括寡糖基转移酶（OST）复合物，作为关键的黄病毒宿主因子。在这里，我们表明，一种称为 NGI-1 的 OST 复合物的化学调节剂对黄病毒感染具有有前途的抗病毒活性。我们证明 NGI-1 阻断病毒 RNA 复制，并且抗病毒活性不依赖于 OST 的 N-糖基化功能的抑制。在缺乏 OST 复合物的细胞中复制适应的病毒突变体对 NGI-1 处理表现出抗性，这加强了 NGI-1 的靶标活性。最后，我们表明 NGI-1 在原代和与疾病相关的细胞类型中也具有很强的抗病毒活性。这项研究为从感染的遗传决定因素进展到针对黄病毒具有广泛活性的宿主定向抗病毒化合物提供了一个范例。
