通过SARS-CoV-2RNA聚合酶和S759A耐药性的选择性remdesivir整合的结构基础
bioRxiv : the preprint server for biology
|September 15, 2025
概括
雷梅西维尔三酸盐 (RTP) 最好通过SARS-CoV-2RNA依赖RNA聚合酶 (RdRp) 而不是ATP结合,但连续的结合受到阻碍. 一个特定的突变 (S759A) 赋予了对RTP的抵抗力.
科学领域:
- 病毒学 病毒学
- 生物化学 生物化学
- 结构生物学 结构生物学
背景情况:
- 核类型 (NA) 是重要的抗病毒药物.
- 像雷梅西维尔这样的NTP类似物通过各种机制抑制病毒聚合酶.
研究的目的:
- 通过SARS-CoV-2RNA依赖RNA聚合酶 (RdRp) 来确定remdesivir三酸盐 (RTP) 与ATP的结合频率.
- 阐明雷梅西维尔抑制机制和耐药性的结构基础.
主要方法:
- 酶性检测试验 酶性检测试验
- 质谱测量质量谱测量
- 低温电子显微镜 (cryo-EM) 是一种电子显微镜.
主要成果:
- 在SARS-CoV-2 RdRp中,RTP优于ATP,即使在10倍低的度下也是如此.
- 由于remdesivir:UMP基对弹性,在ATP存在时,连续的RTP整合是不利的.
- S759A突变通过改变核糖体构造和原料定位来赋予对RTP结合的抗性.
结论:
- RTP的整合依赖于度,并受到结构因素的影响,限制了remdesivir在RNA中的整合.
- 了解这些机制可以了解非强制性的NTP模拟抑制和抵抗.
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