Investigation of novel 5ʹ-amino adenosine derivatives with potential anti-Zika virus activity

• Published in: European journal of medicinal chemistry Vol. 261; p. 115852
• Main Authors: Chen, Xingjuan, Yan, Yunzheng, Song, Huijuan, Wang, Zhuang, Wang, Apeng, Yang, Jingjing, Zhou, Rui, Xu, Shijie, Yang, Shaokang, Li, Wei, Qin, Xiaoyu, Dai, Qingsong, Liu, Mingliang, Lv, Kai, Cao, Ruiyuan, Zhong, Wu
• Format: Journal Article
• Language: English
• Published: Elsevier Masson SAS 05.12.2023
• Subjects: Antiviral agents; MTase; Nucleoside analogs; RdRp; Zika virus; MTase; Antiviral agents; Zika virus; RdRp; Nucleoside analogs
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115852

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. [Display omitted] •5ʹ-amino adenosine derivatives exhibited significant in vitro anti-ZIKV activity.•Compound XSJ2-46 gave potent in vitro activity, with an IC50 value of 2.15 μM.•XSJ2-46 (10 mg/kg/day) showed a 70% survival rate in a ZIKV-infected mice model.•XSJ2-46 significantly reduced serum levels of ZIKV viral RNA in the mice model.