Department of Chemistry, Vanderbilt University, Nashville, TN 37240.
Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN 37240.
Proc Natl Acad Sci U S A. 2021 Jan 19;118(3). doi: 10.1073/pnas.2012209118.
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，是广泛存在的人类病原体；然而，目前还没有广泛有效的治疗方法来对抗感染。最近，通过药理学调节剂（如化合物 147）重塑内质网（ER）蛋白质稳态，被证明可以纠正与蛋白质错误折叠疾病相关的病理性 ER 失衡。在这里，我们确定了化合物 147 的另一种活性，即作为一种有效的针对黄病毒的宿主中心抗病毒药物。化合物 147 通过减弱分泌型病毒粒子的感染力来降低感染，而不会在宿主细胞中引起毒性。化合物 147 是内质网未折叠蛋白反应的 ATF6 途径的优先激活剂，该途径需要主要针对蛋白二硫键异构酶（PDI）上的半胱氨酸残基进行靶向。我们发现，147 的抗病毒活性不依赖于 ATF6 的诱导，但确实需要修饰蛋白靶标上的反应性巯基。使用 RNAi 和其他小分子抑制剂靶向 PDIs 和其他非 PDI 靶标，无法重现抗病毒作用，这表明独特的多药理学可能介导该活性。重要的是，147 可以削弱多种登革热和寨卡病毒株的感染，表明它适合作为一种广谱抗病毒药物。
