Recent outbreaks of Zika virus (ZIKV) highlight an urgent need for therapeutics. The protease complex NS2B-NS3 plays essential roles during flaviviral polyprotein processing, and thus represents an attractive drug target. Here, we developed a split luciferase complementation-based high-throughput screening assay to identify orthosteric inhibitors that directly target flavivirus NS2B-NS3 interactions. By screening a total of 2 816 approved and investigational drugs, we identified three potent candidates, temoporfin, niclosamide, and nitazoxanide, as flavivirus NS2B-NS3 interaction inhibitors with nanomolar potencies. Significantly, the most potent compound, temoporfin, not only inhibited ZIKV replication in human placental and neural progenitor cells, but also prevented ZIKV-induced viremia and mortality in mouse models. Structural docking suggests that temoporfin potentially binds NS3 pockets that hold critical NS2B residues, thus inhibiting flaviviral polyprotein processing in a non-competitive manner. As these drugs have already been approved for clinical use in other indications either in the USA or other countries, they represent promising and easily developed therapies for the management of infections by ZIKV and other flaviviruses.

中文翻译：

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现有药物通过靶向NS2B-NS3相互作用作为Zika病毒的广谱和有效抑制剂。

最近爆​​发的寨卡病毒（ZIKV）突显了对疗法的迫切需求。蛋白酶复合物NS2B-NS3在黄病毒多蛋白加工过程中起着至关重要的作用，因此代表了有吸引力的药物靶标。在这里，我们开发了一种基于荧光素酶补体的高通量筛选检测方法，以鉴定直接靶向黄病毒NS2B-NS3相互作用的正构抑制剂。通过筛选总共2 816种经过批准和研究的药物，我们确定了三种强效候选药物，替莫泊芬，烟酰胺和硝唑尼特，它们是具有纳摩尔效价的黄病毒NS2B-NS3相互作用抑制剂。重要的是，最有效的化合物替莫泊芬不仅抑制人胎盘和神经祖细胞中的ZIKV复制，而且还预防了小鼠模型中ZIKV引起的病毒血症和死亡率。结构性对接表明，替莫泊芬可能结合具有关键NS2B残基的NS3口袋，从而以非竞争性方式抑制黄病毒多蛋白的加工。由于这些药物已经在美国或其他国家/地区被批准用于其他适应症的临床应用，因此它们代表了有希望且易于开发的用于控制ZIKV和其他黄病毒感染的疗法。