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通过非核酸酶抑制剂HeE1-2Tyr抑制SARS-CoV-2聚合酶的结构基础

Florian Kabinger¹, Valerie Doze¹, Jana Schmitzová¹

¹Department of Molecular Biology, Max Planck Institute for Multidisciplinary Sciences, Göttingen 37077, Germany.

Proceedings of the National Academy of Sciences of the United States of America

|March 4, 2025

概括

一种新的小分子HeE1-2Tyr通过与其RNA位点结合来抑制SARS-CoV-2RNA依赖RNA聚合酶 (RdRp). 这一发现可能导致新的泛冠状病毒治疗方法.

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:

针对SARS-CoV-2RNA依赖RNA聚合酶 (RdRp) 的小分子抑制剂为COVID-19提供了一个有前途的治疗途径.
然而,仍然需要强效和安全的抑制剂,并且对HeE1-2Tyr等现有化合物的作用机制尚未完全理解.

研究的目的:

阐明HeE1-2Tyr抑制SARS-CoV-2 RdRp的分子机制.
研究HeE1-2Tyr的潜力,作为开发泛冠状病毒非核酸抑制剂的基础.

主要方法:

生物化学测试用于确定HeE1-2Tyr对SARS-CoV-2 RdRp的抑制度 (IC50) 并评估其与RNA结合的相互作用.
使用冷电子显微镜 (cryo-EM) 可视化了HeE1-2Tyr与RdRp结合的结构基础.

主要成果:

证实HeE1-2Tyr可以抑制SARS-CoV-2 RdRp,其IC50为5μM.
生物化学分析表明,HeE1-2Tyr与RNA竞争,以与RdRp结合.
低温EM检测显示,三个堆叠的HeE1-2Tyr分子在RdRp的RNA结合部位内结合.

结论:

HeE1-2Tyr以一种独特的方式与RNA结合部位结合,从而抑制SARS-CoV-2 RdRp,其中涉及三个堆叠的分子.
鉴定这种保存的结合位点和抑制机制可以指导新型,广泛的冠状病毒非核酸抑制剂的开发.

关键词:

这是一种依赖RNA的RNA聚合酶.这就是SARS-CoV-2病毒.低温电磁波冷却器 (Cryo-EM) 是一个非常好的方法.非核酸抑制剂的非核酸抑制剂

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