Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen.
Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen.
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DOI：
10.1038/nm.4184
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发表时间：
2016-10
期刊：
影响因子：
82.9
通讯作者：
Tang H
中科院分区：
文献类型：
--
作者：
Xu M;Lee EM;Wen Z;Cheng Y;Huang WK;Qian X;Tcw J;Kouznetsova J;Ogden SC;Hammack C;Jacob F;Nguyen HN;Itkin M;Hanna C;Shinn P;Allen C;Michael SG;Simeonov A;Huang W;Christian KM;Goate A;Brennand KJ;Huang R;Xia M;Ming GL;Zheng W;Song H;Tang H
为了应对寨卡病毒（ZIKV）爆发及其与小头畸形和其他神经系统疾病的联系所造成的当前全球卫生紧急情况，我们对约6，000种化合物进行了药物再利用筛选，其中包括批准的药物，临床试验候选药物和非活性化合物，并且我们鉴定了在不同神经细胞中抑制ZIKV感染或抑制感染诱导的caspase-3活性的化合物。泛半胱天冬酶抑制剂Emricasan抑制ZIKV诱导的半胱天冬酶-3活性增加，并在单层和三维类器官培养物中保护人皮质神经祖细胞。10种结构上不相关的细胞周期蛋白依赖性激酶抑制剂抑制ZIKV复制。FDA批准的B类驱虫药氯硝柳胺也抑制ZIKV复制。最后，使用来自每个类别（神经保护和抗病毒）的一种化合物的组合治疗进一步增加了对人神经祖细胞和星形胶质细胞免于ZIKV诱导的细胞死亡的保护。我们的结果证明了这种筛选策略的有效性，并鉴定了用于抗ZIKV药物开发的先导化合物。
In response to the current global health emergency posed by the Zika virus (ZIKV) outbreak and its link to microcephaly and other neurological conditions, we performed a drug repurposing screen of ~6,000 compounds that included approved drugs, clinical trial drug candidates and pharmacologically active compounds, and we identified compounds that either inhibit ZIKV infection or suppress infection-induced caspase-3 activity in different neural cells. A pan-caspase inhibitor, Emricasan, inhibited ZIKV-induced increases in caspase-3 activity and protected human cortical neural progenitors in both monolayer and 3-dimensional organoid cultures. Ten structurally unrelated inhibitors of cyclin-dependent kinases inhibited ZIKV replication. Niclosamide, an FDA approved category B anthelmintic drug, also inhibited ZIKV replication. Finally, combination treatments using one compound from each category (neuroprotective and antiviral) further increased protection of human neural progenitors and astrocytes from ZIKV-induced cell death. Our results demonstrate the efficacy of this screening strategy and identify lead compounds for anti-ZIKV drug development.