Antiviral Activity of Compound L3 against Dengue and Zika Viruses In Vitro and In Vivo
Antiviral Activity of Compound L3 against Dengue and Zika Viruses In Vitro and In Vivo
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DOI：
10.3390/ijms21114050
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发表时间：
2020-06-01
影响因子：
5.6
通讯作者：
Yen, Li-Chen
中科院分区：
文献类型：
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作者：
Chuang, Fu-Kai;Liao, Ching-Len;Yen, Li-Chen
登革热病毒（DENV）和寨卡病毒（ZIKV）是蚊媒黄病毒，感染后会导致严重疾病。目前，还没有针对DENV和ZIKV的特异性或有效的治疗方法。先前的研究已经表明酪氨酸激酶活性和信号转导参与黄病毒复制，这表明DENV和ZIKV的潜在治疗策略。在这项研究中，我们发现化合物L3可以显著降低HEK-293、MCF-7、HepG 2和Huh-7细胞中的病毒蛋白表达和病毒滴度，并且与其他酪氨酸激酶抑制剂相比，对黄病毒感染表现出上级治疗功效。此外，化合物L3可降低内源性HER 2活化并抑制HER 2下游信号传导分子Src和ERK 1/2的磷酸化，其水平与MCF-7细胞中的病毒蛋白表达相关。此外，沉默HER 2减少了MCF-7细胞中的DENV-2和ZIKV表达，这表明HER 2活性参与黄病毒复制。此外，在DENV-2感染的AG 129小鼠中，用化合物L3治疗增加了存活率并降低了病毒血症水平。总体而言，化合物L3在体外和体内均表现出治疗功效，并且可以开发为针对新出现的黄病毒或同时发生的DENV和ZIKV爆发的有前景的抗病毒药物。
Dengue virus (DENV) and Zika virus (ZIKV) are mosquito-borne flaviviruses that cause severe illness after infection. Currently, there are no specific or effective treatments against DENV and ZIKV. Previous studies have shown that tyrosine kinase activities and signal transduction are involved in flavivirus replication, suggesting a potential therapeutic strategy for DENV and ZIKV. In this study, we found that compound L3 can significantly reduce viral protein expression and viral titers in HEK-293, MCF-7, HepG2, and Huh-7 cells and exhibits superior therapeutic efficacy against flaviviral infection compared to other tyrosine kinase inhibitors. In addition, compound L3 can decrease endogenous HER2 activation and inhibit the phosphorylation of the HER2 downstream signaling molecules Src and ERK1/2, the levels of which have been associated with viral protein expression in MCF-7 cells. Moreover, silencing HER2 diminished DENV-2 and ZIKV expression in MCF-7 cells, which suggests that HER2 activity is involved in flavivirus replication. Furthermore, in DENV-2-infected AG129 mice, treatment with compound L3 increased the survival rates and reduced the viremia levels. Overall, compound L3 demonstrates therapeutic efficacy both in vitro and in vivo and could be developed as a promising antiviral drug against emerging flaviviruses or for concurrent DENV and ZIKV outbreaks.