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

  • Eur J Med Chem. 2023 Oct 1:261:115852. doi: 10.1016/j.ejmech.2023.115852.
Xingjuan Chen  1 ,  Yunzheng Yan  2 ,  Huijuan Song  3 ,  Zhuang Wang  1 ,  Apeng Wang  3 ,  Jingjing Yang  4 ,  Rui Zhou  3 ,  Shijie Xu  3 ,  Shaokang Yang  2 ,  Wei Li  2 ,  Xiaoyu Qin  3 ,  Qingsong Dai  2 ,  Mingliang Liu  3 ,  Kai Lv  5 ,  Ruiyuan Cao  6 ,  Wu Zhong  7
Affiliations
  • 1. Institute of Medical Research, Northwestern Polytechnical University, Xi'an, Shannxi, 710072, China; National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China.
  • 2. National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China.
  • 3. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • 4. Song Li' Academician Workstation of Hainan University (School of Pharmaceutical Sciences), Sanya, Hainan, 572000, China.
  • 5. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: [email protected].
  • 6. National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China. Electronic address: [email protected].
  • 7. National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China. Electronic address: [email protected].
PMID: 37801825 DOI: 10.1016/j.ejmech.2023.115852
Abstract

The Zika virus (ZIKV) infections remains a global health threat. However, no approved drug for treating ZIKV Infection. We previously found TZY12-9, a 5'-amino NI analog, that showed anti-ZIKV activity without chemical phosphorylation. Here, a series of 5'-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 5'-amino NI structure skeleton for developing Antiviral NIs.

Keywords
Antiviral agents; MTase; Nucleoside analogs; RdRp; Zika virus.
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