S119 was a top hit from an ultrahigh throughput screen performed to identify novel inhibitors of influenza virus replication. It showed a potent antiviral effect (50% inhibitory concentration, IC50 = 20 nM) and no detectable cytotoxicity (50% cytotoxic concentration, CC50 > 500 μM) to yield a selectivity index greater than 25 000. Upon investigation, we found that S119 selected for resistant viruses carrying mutations in the viral nucleoprotein (NP). These resistance mutations highlight a likely S119 binding site overlapping with but not identical to that found for the compound nucleozin. Mechanism of action studies revealed that S119 affects both the oligomerization state and cellular localization of the NP protein which has an impact on viral transcription, replication, and protein expression. Through a hit-to-lead structure-activity relationship (SAR) study, we found an analog of S119, named S119-8, which had increased breadth of inhibition against influenza A and B viruses accompanied by only a small loss in potency. Finally, in vitro viral inhibition assays showed a synergistic relationship between S119-8 and oseltamivir when they were combined, indicating the potential for future drug cocktails.

中文翻译：

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靶向病毒核蛋白的甲型和乙型流感病毒的广谱抑制剂。

S119是超高通量筛选的热门影片，该筛选用于鉴定新型流感病毒复制抑制剂。它显示出有效的抗病毒作用（50％抑制浓度，IC50 = 20 nM），没有可检测到的细胞毒性（50％细胞毒性浓度，CC50> 500μM），产生的选择性指数大于25000。经研究，我们发现选择了S119用于携带病毒核蛋白（NP）突变的抗性病毒。这些抗性突变突显出可能的S119结合位点与化合物核苷发现的位点重叠但不相同。作用机理研究表明，S119影响NP蛋白的低聚状态和细胞定位，这对病毒的转录，复制和蛋白表达都有影响。通过铅-铅之间的结构-活性关系（SAR）研究，我们发现了名为S119-8的S119类似物，其对甲型和乙型流感病毒的抑制作用范围增加，而效力却仅有很小的损失。最后，体外病毒抑制试验显示，当S119-8和奥司他韦合并使用时，它们之间具有协同关系，表明将来有可能成为药物混合物。