研究具有潜在抗寨卡病毒活性的新型5'-氨基腺酸衍生物
Xingjuan Chen1, Yunzheng Yan2, Huijuan Song3
1Institute 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.
European journal of medicinal chemistry
|October 6, 2023
概括
一种新化合物,XSJ2-46,显示出强大的潜力,作为一种抗病毒治疗寨卡病毒 (ZIKV) 感染. 这种5'-氨基NI类似物在体外和体内有效抑制ZIKV复制,提供了一个有前途的治疗方向.
科学领域:
- 病毒学 病毒学
- 药用化学 医学化学
- 药物发现 药物发现 药物发现
背景情况:
- 寨卡病毒 (ZIKV) 感染对全球健康构成重大风险.
- 目前,没有批准的抗病毒药物用于ZIKV治疗.
- 之前的研究发现了TZY12-9,一种具有抗ZIKV活性的5 -amino NI类似物.
研究的目的:
- 为了合成和评估抗ZIKV活性的新型5 -amino NI类似物.
- 研究有前途的化合物的作用机制和体内疗效.
- 探索5 - 氨基NI类似物作为一种新类抗病毒药物的潜力.
主要方法:
- 合成和体外评价5 -amino NI类似物与ZIKV.
- 对化合物的药理动力学和急性毒性评估.
- ZIKV非结构蛋白抑制试验和宿主细胞RNA测序 (RNA-seq).
- 在感染ZIKV的小鼠模型中的体内疗效研究 (ICR和Ifnar-/- A129).
主要成果:
- 化合物XSJ2-46在体外表现出强大的抗ZIKV活性,而不需要化学酸化.
- XSJ2-46表现出有利的药理动力学和急性毒性概况.
- 该化合物通过向具有IC50为8.78μM的RNA依赖RNA聚合酶 (RdRp) 来抑制ZIKV复制.
- 在受感染的小鼠中,XSJ2-46治疗显著改善了生存率,并降低了病毒RNA水平.
- RNA-seq分析表明细胞因子和细胞因子受体通路的调节.
结论:
- 化合物XSJ2-46在体外和体内显示出显著的抗ZIKV疗效.
- 5 - 氨基尼基基基架构代表了开发针对ZIKV的新型抗病毒药物的有前途的结构框架.
- 对XSJ2-46和相关化合物的进一步研究是治疗开发的必要条件.
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