2. Academic Validation
  3. Investigation of novel 5'-amino adenosine derivatives with potential anti-Zika virus activity

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

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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