SARS-CoV-2 3CLpro 对非共价抑制剂 WU-04 的抗药性机制

IF 13 1区 生物学 Q1 CELL BIOLOGY Cell Discovery Pub Date : 2024-04-09 DOI:10.1038/s41421-024-00673-0
Lijing Zhang, Xuping Xie, Hannan Luo, Runtong Qian, Yang Yang, Hongtao Yu, Jing Huang, Pei-Yong Shi, Qi Hu
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摘要

耐药性是开发抗 SARS-CoV-2 有效疗法的重大挑战。在这里,我们发现了 3C 样蛋白酶(3CLpro)中的两个双突变 M49K/M165V 和 M49K/S301P,这两个突变使其对新型非共价抑制剂 WU-04 产生了耐药性,WU-04 目前正在进行 III 期临床试验 (NCT06197217)。晶体学分析表明,M49K 突变破坏了 WU-04 结合口袋的稳定性,对 WU-04 结合的影响比对 3CLpro 底物结合的影响更大。M165V 突变直接干扰了 WU-04 的结合。远离 WU-04 结合口袋的 S301P 突变通过限制 3CLpro C 端尾部的旋转和阻碍 3CLpro 的二聚化间接影响了 WU-04 的结合。我们进一步探究了使 3CLpro 对两种临床使用的抑制剂(ensitrelvir 和 nirmatrelvir)产生耐药性的 3CLpro 突变,发现 3CLpro 的催化活性、热稳定性和耐药性之间存在权衡。我们发现,同一个残基(M49)的突变会对 3CLpro 抑制剂产生不同的影响,这凸显了开发具有不同骨架的多种抗病毒药物来对抗 SARS-CoV-2 的重要性。这些发现加深了我们对 SARS-CoV-2 抗药性机制的了解,为开发有效的治疗药物提供了依据。
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Resistance mechanisms of SARS-CoV-2 3CLpro to the non-covalent inhibitor WU-04

Drug resistance poses a significant challenge in the development of effective therapies against SARS-CoV-2. Here, we identified two double mutations, M49K/M165V and M49K/S301P, in the 3C-like protease (3CLpro) that confer resistance to a novel non-covalent inhibitor, WU-04, which is currently in phase III clinical trials (NCT06197217). Crystallographic analysis indicates that the M49K mutation destabilizes the WU-04-binding pocket, impacting the binding of WU-04 more significantly than the binding of 3CLpro substrates. The M165V mutation directly interferes with WU-04 binding. The S301P mutation, which is far from the WU-04-binding pocket, indirectly affects WU-04 binding by restricting the rotation of 3CLpro’s C-terminal tail and impeding 3CLpro dimerization. We further explored 3CLpro mutations that confer resistance to two clinically used inhibitors: ensitrelvir and nirmatrelvir, and revealed a trade-off between the catalytic activity, thermostability, and drug resistance of 3CLpro. We found that mutations at the same residue (M49) can have distinct effects on the 3CLpro inhibitors, highlighting the importance of developing multiple antiviral agents with different skeletons for fighting SARS-CoV-2. These findings enhance our understanding of SARS-CoV-2 resistance mechanisms and inform the development of effective therapeutics.

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来源期刊
Cell Discovery
Cell Discovery Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
24.20
自引率
0.60%
发文量
120
审稿时长
20 weeks
期刊介绍: Cell Discovery is a cutting-edge, open access journal published by Springer Nature in collaboration with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). Our aim is to provide a dynamic and accessible platform for scientists to showcase their exceptional original research. Cell Discovery covers a wide range of topics within the fields of molecular and cell biology. We eagerly publish results of great significance and that are of broad interest to the scientific community. With an international authorship and a focus on basic life sciences, our journal is a valued member of Springer Nature's prestigious Molecular Cell Biology journals. In summary, Cell Discovery offers a fresh approach to scholarly publishing, enabling scientists from around the world to share their exceptional findings in molecular and cell biology.
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