SARS-CoV-2校对酶介导的瑞德西韦耐药性的分子基础

IF 9.1 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-01 DOI:10.1073/pnas.2519755122

Yang Yang, Yu Li, Scott T. Becker, Ayesha Khan, Gloria Luo, Bin Liu, Chang Liu

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引用次数: 0

摘要

SARS-CoV-2对核苷酸类似抗病毒药物（如通过抑制病毒聚合酶（RdRp）阻碍RNA合成的remdesivir）具有显著的耐药性，这对现有的治疗方法构成了挑战。我们发现，瑞德西韦掺入破坏了RdRp-RNA复合物的稳定性，同时增强了RNA与校对外核糖核酸酶（ExoN）的结合，促进了瑞德西韦的切除。瑞德西韦识别和切除的保守外显子决定因素是所有冠状病毒外显子介导耐药性的基础。这些发现为设计能够克服外显子介导的耐药的下一代抗病毒药物和联合疗法提供了信息。

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Molecular basis of SARS-CoV-2 proofreading enzyme–mediated resistance to remdesivir

SARS-CoV-2’s remarkable resistance to nucleotide analog antivirals such as remdesivir, which thwarts RNA synthesis by inhibiting viral polymerase (RdRp), challenges available therapies. We reveal that remdesivir incorporation destabilizes RdRp–RNA complex while enhancing RNA binding to the proofreading exoribonuclease (ExoN), facilitating remdesivir excision. Conserved ExoN determinants for remdesivir recognition and excision underpin ExoN-mediated resistance across all coronaviruses. These findings inform the design of next-generation antivirals and combination therapies capable of overcoming ExoN-mediated resistance.

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来源期刊

Proceedings of the National Academy of Sciences of the United States of America 综合性期刊-综合性期刊

CiteScore

19.00

自引率

0.90%

发文量

3575

审稿时长

2.5 months

期刊介绍： The Proceedings of the National Academy of Sciences (PNAS), a peer-reviewed journal of the National Academy of Sciences (NAS), serves as an authoritative source for high-impact, original research across the biological, physical, and social sciences. With a global scope, the journal welcomes submissions from researchers worldwide, making it an inclusive platform for advancing scientific knowledge.