| Discovery of ZFD-10 of a pyridazino[4,5-b]indol-4(5H)-one derivative as an anti-ZIKV agent and a ZIKV NS5 RdRp inhibitor |
| Zhou, GF; Qian, WY; Li, F; Yang, RH; Wang, N; Zheng, CB; Li, CY; Gu, XR; Yang, LM; Liu, JS; Xiong, SD; Zhou, GC; Zheng, YT
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| 2023
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| 发表期刊 | ANTIVIRAL RESEARCH
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| ISSN | 0166-3542
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| 卷号 | 214 |
| 摘要 | Zika virus (ZIKV) infection is associated with the birth defect microcephaly and Guillain-Barre ' syndrome in adults. There is no approved vaccine or specific antiviral agent against ZIKV. ZFD-10, a novel structural skeleton of 1H-pyridazino[4,5-b]indol-4(5H)-one, was firstly synthesized and discovered to be a potent anti-ZIKV in-hibitor with very low cytotoxicity. ZFD-10's anti-ZIKV potency is independent of cell lines and ZFD-10 mainly targets the post-entry stages of ZIKV life cycle. Time-of-addition and time-of-withdrawal assays showed that 10 mu M ZFD-10 displayed the ability to decrease mainly at the RNA level and weakly the viral progeny particle load. Furthermore, ZFD-10 could protect ZIKV NS5 from thermal unfolding and aggregation and increase the Tagg value of ZIKV NS5 protein from 44.6 to 49.3 degrees C, while ZFD-10 dose-dependently inhibits ZIKV NS5 RdRp activity using in vitro RNA polymerase assays. Molecular docking study suggests that ZFD-10 affects RdRp enzymatic function through interfering with the fingers and thumb subdomains. These results supported that ZFD-10's cell-based anti-ZIKV activity is related to its anti-RdRp activity of ZIKV NS5. The in vivo anti-ZIKV study shows that the middle-dose (4.77 mg/kg/d) of ZFD-10 protected mice from ZIKV infection and the viral loads of the blood, liver, kidney and brain in the middle-dose and high-dose (9.54 mg/kg/d) were significantly reduced compared to those of the ZIKV control. These results confirm that ZFD-10 has a certain antiviral effect against ZIKV infection in vivo. |
| 收录类别 | SCI
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| 语种 | 英语
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| 文献类型 | 期刊论文
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| 条目标识符 | http://ir.kiz.ac.cn/handle/152453/13965
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| 专题 | 科研部门_分子免疫药理学（郑永唐）
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推荐引用方式
GB/T 7714 |
Zhou, GF,Qian, WY,Li, F,et al. Discovery of ZFD-10 of a pyridazino[4,5-b]indol-4(5H)-one derivative as an anti-ZIKV agent and a ZIKV NS5 RdRp inhibitor[J]. ANTIVIRAL RESEARCH,2023,214.
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| APA |
Zhou, GF.,Qian, WY.,Li, F.,Yang, RH.,Wang, N.,...&Zheng, YT.(2023).Discovery of ZFD-10 of a pyridazino[4,5-b]indol-4(5H)-one derivative as an anti-ZIKV agent and a ZIKV NS5 RdRp inhibitor.ANTIVIRAL RESEARCH,214.
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| MLA |
Zhou, GF,et al."Discovery of ZFD-10 of a pyridazino[4,5-b]indol-4(5H)-one derivative as an anti-ZIKV agent and a ZIKV NS5 RdRp inhibitor".ANTIVIRAL RESEARCH 214(2023).
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