Existing drugs as broad-spectrum and potent inhibitors for Zika virus by targeting NS2B-NS3 interaction
Existing drugs as broad-spectrum and potent inhibitors for Zika virus by targeting NS2B-NS3 interaction
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DOI：
10.1038/cr.2017.88
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发表时间：
2017-08-01
期刊：
影响因子：
44.1
通讯作者：
Li, Hongmin
中科院分区：
文献类型：
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作者：
Li, Zhong;Brecher, Matthew;Li, Hongmin
最近寨卡病毒(ZIKV)的暴发突显了对疗法的迫切需要。蛋白酶复合体NS2B-NS3在黄病毒多蛋白加工过程中起着至关重要的作用，因此是一个有吸引力的药物靶点。在这里，我们发展了一种基于裂解荧光素酶互补的高通量筛选方法来鉴定直接针对黄病毒NS2B-NS3相互作用的正构体抑制剂。通过对2816种已批准和正在研究的药物的筛选，我们确定了三种有效的候选药物：替普芬、氯硝柳胺和硝唑尼特，它们是黄病毒NS2B-NS3相互作用的抑制物，具有纳摩尔效力。值得注意的是，最有效的化合物替普芬不仅抑制了ZIKV在人类胎盘和神经前体细胞中的复制，而且还防止了ZIKV诱导的病毒血症和小鼠模型中的死亡。结构对接表明，替普芬可能结合了持有关键NS2B残基的NS3口袋，从而以非竞争性的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被批准用于其他适应症的临床应用，它们代表着很有前途的、易于开发的治疗ZIKV和其他黄病毒感染的方法。
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.