普罗利尔tRNA合成酶是哺乳动物病毒繁殖所需的
bioRxiv : the preprint server for biology
|February 9, 2026
概括
黄 (HF) 通过向林-tRNA合成酶活性,有效抑制乳腺病毒 (MaAv),包括拉萨病毒和朱宁病毒. 这种抗病毒药物对治疗由这些危险的RNA病毒引起的感染有前途.
科学领域:
- 病毒学 病毒学
- 分子生物学分子生物学
- 药物发现 药物发现 药物发现
背景情况:
- 乳腺病毒 (MaAv),如拉萨病毒 (LASV) 和朱宁病毒 (JUNV),导致严重的人类疾病,并在流行地区引起严重的公共卫生问题.
- 淋巴细胞胆膜炎病毒 (LCMV),另一个MaAv,是一个未被认可的病原体,特别危险的免疫力低下的人和先天性感染.
- 对抗致病性MaAv的新型抗病毒药物非常需要,因为目前的利巴维林等治疗方法的疗效有限且有争议,并且没有FDA批准的疫苗或抗病毒药物.
研究的目的:
- 调查Halofuginone (HF) 对人类致病性乳腺病毒 (MaAv) 的抗病毒活性.
- 阐明HF对MaAv的作用机制,重点关注其与宿主细胞机械的相互作用.
主要方法:
- 对HF进行了剂量依赖的抗病毒活性测定,针对LCMV,LASV和JUNV.
- 分析了HF与宿主酶谷氨基烯酸-tRNA合成酶1 (EPRS1) 的相互作用及其对烯酸-tRNA合成酶 (PRS) 活性的特定抑制.
- 评估了HF对病毒复制的影响,包括细胞进入,病毒核糖蛋白 (vRNP) 活性和Z蛋白芽. 通过添加外源性来挽救HF的抗病毒作用来检查的作用.
主要成果:
- 黄 (Halofuginone,简称HF) 对LCMV,LASV和JUNV表现出强有力的,剂量依赖的抗病毒活性.
- HF抑制了双功能酶EPRS1的prolyl-tRNA合成酶 (PRS) 活性,通过氨基酸饥饿 (AAS) 反应导致翻译抑制,特别是影响富含proline的蛋白质.
- HF对LCMV的抗病毒效应被外源性普罗林逆转,证实了PRS抑制的关键作用.
- 高风并没有阻碍LCMV细胞进入,但适度降低了vRNP活性,并强烈抑制了 (>90%) Z蛋白芽,这是病毒释放至关重要的过程.
结论:
- 黄 (HF) 是一种强大的抗病毒剂,通过抑制宿主细胞prolyl-tRNA合成酶 (PRS) 活性,对临床显著的乳腺病毒 (MaAv) 起作用.
- 该机制涉及氨基酸饥饿和对富含proline的蛋白质的优先影响,这些蛋白质对于像Z芽生长这样的病毒过程至关重要.
- HF代表了一种有前途的治疗候选药物,用于治疗由致病性MaAv引起的感染,解决重大未满足的医疗需求.
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