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Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir | |
2022-11-09 | |
发表期刊 | NATURE |
ISSN | 0028-0836 |
EISSN | 1476-4687 |
发表状态 | 已发表 |
DOI | 10.1038/s41586-022-05514-2 |
摘要 | Nirmatrelvir, an oral antiviral targeting the 3CL protease of SARS-CoV-2, has been demonstrated to be clinically useful against COVID-19 (refs. (1,2)). However, because SARS-CoV-2 has evolved to become resistant to other therapeutic modalities(3-9), there is a concern that the same could occur for nirmatrelvir. Here we examined this possibility by in vitro passaging of SARS-CoV-2 in nirmatrelvir using two independent approaches, including one on a large scale. Indeed, highly resistant viruses emerged from both and their sequences showed a multitude of 3CL protease mutations. In the experiment peformed with many replicates, 53 independent viral lineages were selected with mutations observed at 23 different residues of the enzyme. Nevertheless, several common mutational pathways to nirmatrelvir resistance were preferred, with a majority of the viruses descending from T21I, P252L or T304I as precursor mutations. Construction and analysis of 13 recombinant SARS-CoV-2 clones showed that these mutations mediated only low-level resistance, whereas greater resistance required accumulation of additional mutations. E166V mutation conferred the strongest resistance (around 100-fold), but this mutation resulted in a loss of viral replicative fitness that was restored by compensatory changes such as L50F and T21I. Our findings indicate that SARS-CoV-2 resistance to nirmatrelvir does readily arise via multiple pathways in vitro, and the specific mutations observed herein form a strong foundation from which to study the mechanism of resistance in detail and to inform the design of next-generation protease inhibitors. |
URL | 查看原文 |
收录类别 | SCI ; SCOPUS |
语种 | 英语 |
WOS研究方向 | Science & Technology - Other Topics |
WOS类目 | Multidisciplinary Sciences |
WOS记录号 | WOS:000901944300001 |
出版者 | NATURE PORTFOLIO |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/243571 |
专题 | 生命科学与技术学院 生命科学与技术学院_博士生 免疫化学研究所_PI研究组_杨海涛组 |
共同第一作者 | Mohri, Hiroshi; Culbertson, Bruce; Hong, Seo Jung |
通讯作者 | Chavez, Alejandro; Ho, David D. |
作者单位 | 1.Columbia Univ, Vagelos Coll Phys & Surg, Aaron Diamond AIDS Res Ctr, New York, NY 10032 USA 2.Columbia Univ, Vagelos Coll Phys & Surg, Div Infect Dis, Dept Med, New York, NY 10032 USA 3.Columbia Univ, Vagelos Coll Phys & Surg, Integrated Program Cellular Mol & Biomed Studies, New York, NY 10032 USA 4.Columbia Univ, Vagelos Coll Phys & Surg, Med Scientist Training Program, New York, NY USA 5.Columbia Univ, Vagelos Coll Phys & Surg, Dept Pathol & Cell Biol, New York, NY 10032 USA 6.ShanghaiTech Univ, Shanghai Inst Adv Immunochemicat Studies, Shanghai, Peoples R China 7.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 8.Columbia Univ, Dept Microbiol & Immunol, Vagelos Coll Phys & Surg, New York, NY 10032 USA 9.Columbia Univ, Dept Biochem & Mol Biophys, Vagelos Coll Phys & Surg, New York, NY USA |
推荐引用方式 GB/T 7714 | Iketani, Sho,Mohri, Hiroshi,Culbertson, Bruce,et al. Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir[J]. NATURE,2022. |
APA | Iketani, Sho.,Mohri, Hiroshi.,Culbertson, Bruce.,Hong, Seo Jung.,Duan, Yinkai.,...&Ho, David D..(2022).Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir.NATURE. |
MLA | Iketani, Sho,et al."Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir".NATURE (2022). |
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