寨卡病毒
化学
黄病毒
腺苷
病毒学
病毒
立体化学
生物化学
生物
作者
Xingjuan Chen,Yunzheng Yan,Huijuan Song,Zhuang Wang,Apeng Wang,Jingjing Yang,Rui Zhou,Shijie Xu,Shaokang Yang,Wei Li,Xiaoyu Qin,Qingsong Dai,Mingliang Liu,Kai Lv,Ruiyuan Cao,Wu Zhong
标识
DOI:10.1016/j.ejmech.2023.115852
摘要
The Zika virus (ZIKV) infections remains a global health threat. However, no approved drug for treating ZIKV infection. We previously found TZY12-9, a 5ʹ-amino NI analog, that showed anti-ZIKV activity without chemical phosphorylation. Here, a series of 5ʹ-amino NI analogs were synthesized and evaluated. The compound XSJ2-46 exhibited potent in vitro activity without requiring chemical phosphorylation, favorable pharmacokinetic and acute toxicity profiles. Preliminary mechanisms of anti-ZIKV activity of XSJ2-46 were investigated via a series of ZIKV non-structural protein inhibition assays and host cell RNA-seq. XSJ2-46 acted at the replication stage of viral infection cycle, and exhibited reasonable inhibition of RNA-dependent RNA polymerases (RdRp) with an IC50 value of 8.78 μM, while not affecting MTase. RNA-seq analysis also revealed differential expression genes involved in cytokine and cytokine receptor pathway in ZIKV-infected U87 cells treated with XSJ2-46. Importantly, treatment with XSJ2-46 (10 mg/kg/day) significantly enhanced survival protection (70% survival) in ZIKV-infected ICR mice. Additionally, XSJ2-46 administration resulted in a significant decrease in serum levels of ZIKV viral RNA in the IFNα/β receptor-deficient (Ifnar−/−) A129 mouse model. Therefore, the remarkable in vitro and in vivo anti-ZIKV activity of compound XSJ2-46 highlights the promising research direction of utilizing the 5ʹ-amino NI structure skeleton for developing antiviral NIs.
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