Flaviviruses, including dengue and Zika, are widespread human pathogens; however, no broadly active therapeutics exist to fight infection. Recently, remodeling of endoplasmic reticulum (ER) proteostasis by pharmacologic regulators, such as compound 147, was shown to correct pathologic ER imbalances associated with protein misfolding diseases. Here, we establish an additional activity of compound 147 as an effective host-centered antiviral agent against flaviviruses. Compound 147 reduces infection by attenuating the infectivity of secreted virions without causing toxicity in host cells. Compound 147 is a preferential activator of the ATF6 pathway of the ER unfolded protein response, which requires targeting of cysteine residues primarily on protein disulfide isomerases (PDIs). We find that the antiviral activity of 147 is independent of ATF6 induction but does require modification of reactive thiols on protein targets. Targeting PDIs and additional non-PDI targets using RNAi and other small-molecule inhibitors was unable to recapitulate the antiviral effects, suggesting a unique polypharmacology may mediate the activity. Importantly, 147 can impair infection of multiple strains of dengue and Zika virus, indicating that it is suitable as a broad-spectrum antiviral agent.

黄病毒包括登革热和寨卡病毒是广泛的人类病原体。但是，尚无抗感染的广泛活性疗法。最近，已显示通过药理调节剂（例如化合物147）对内质网（ER）蛋白质稳态的重塑可纠正与蛋白错误折叠疾病相关的病理性ER失衡。在这里，我们建立了化合物147作为抗黄病毒的有效的以宿主为中心的抗病毒剂的附加活性。化合物147通过减弱分泌的病毒体的感染力而减少感染，而不会在宿主细胞中引起毒性。化合物147是ER未折叠蛋白应答的ATF6途径的优先激活剂，其需要主要在蛋白二硫键异构酶（PDI）上靶向半胱氨酸残基。我们发现147的抗病毒活性独立于ATF6诱导，但确实需要对蛋白质靶标上的反应性硫醇进行修饰。使用RNAi和其他小分子抑制剂靶向PDI和其他非PDI靶不能概括抗病毒作用，表明独特的多药理学可以介导该活性。重要的是，147可以削弱多株登革热和寨卡病毒的感染，表明它适合用作广谱抗病毒药。