Institute of Human Virology, Sun Yat-Sen University, Guangzhou, Guangdong, China.
Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China.
J Virol. 2018 Sep 26;92(20). doi: 10.1128/JVI.01018-18. Print 2018 Oct 15.
Zika virus (ZIKV) is genetically and biologically related to other family members and has disseminated to many countries. It is associated with severe consequences, including the abnormal development of the neural system in fetuses and neurological diseases in adults. Therefore, the development of anti-ZIKV drugs is of paramount importance. Screening of generic drugs revealed that several nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, ibuprofen, naproxen, acetaminophen, and lornoxicam, potently inhibited the entry of Zika virus Env/HIV-1-pseudotyped viruses. They also significantly inhibited the replication of wild-type ZIKV both in cell lines and in primary human fetal endothelial cells. Interestingly, the NSAIDs exerted this inhibitory effect by potently reducing the expression of AXL, the entry cofactor of ZIKV. Further studies showed that the NSAIDs downregulated the prostaglandin E/prostaglandin E receptor 2 (EP2)/cAMP/protein kinase A (PKA) signaling pathway and reduced PKA-dependent CDC37 phosphorylation and the interaction between CDC37 and HSP90, which subsequently facilitated CHIP/ubiquitination/proteasome-mediated AXL degradation. Taken together, our results highlight a new mechanism of action of antiviral agents which may assist in designing a convenient strategy for treating ZIKV-infected patients. Zika virus (ZIKV) infection, which causes congenital malformations, including microcephaly and other neurological disorders, has attracted global attention. We observed that several NSAIDs significantly inhibited ZIKV infection. Based on our observations, we propose a novel mechanism of action of antiviral compounds which involves the blockade of virus entry via degradation of the entry cofactor. Furthermore, NSAIDs can be practically used for preventing ZIKV infection in pregnant women, as certain NSAIDs, including ibuprofen and acetaminophen, are considered clinically safe.
寨卡病毒（ZIKV）在基因和生物学上与其他家族成员有关，并已传播到许多国家。它与严重后果有关，包括胎儿神经系统的异常发育和成人的神经疾病。因此，开发抗 ZIKV 药物至关重要。对普通药物的筛选表明，几种非甾体抗炎药（NSAIDs），包括阿司匹林、布洛芬、萘普生、对乙酰氨基酚和洛索洛芬，能有效抑制寨卡病毒包膜/艾滋病毒-1 假型病毒的进入。它们还显著抑制野生型 ZIKV 在细胞系和原代人胎内皮细胞中的复制。有趣的是，NSAIDs 通过强烈降低 ZIKV 的进入辅助因子 AXL 的表达来发挥这种抑制作用。进一步的研究表明，NSAIDs 下调了前列腺素 E/前列腺素 E 受体 2（EP2）/cAMP/蛋白激酶 A（PKA）信号通路，降低了 PKA 依赖的 CDC37 磷酸化和 CDC37 与 HSP90 的相互作用，从而促进 CHIP/泛素化/蛋白酶体介导的 AXL 降解。综上所述，我们的研究结果强调了抗病毒药物的一种新作用机制，这可能有助于设计一种治疗 ZIKV 感染患者的便捷策略。寨卡病毒（ZIKV）感染可导致先天性畸形，包括小头畸形和其他神经障碍，引起了全球关注。我们观察到几种 NSAIDs 能显著抑制 ZIKV 感染。基于我们的观察，我们提出了一种抗病毒化合物的新作用机制，该机制涉及通过降解进入辅助因子来阻断病毒进入。此外，NSAIDs 可实际用于预防孕妇感染 ZIKV，因为某些 NSAIDs，包括布洛芬和对乙酰氨基酚，被认为在临床上是安全的。
