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Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir

Author

Listed:
  • Sho Iketani

    (Columbia University Vagelos College of Physicians and Surgeons
    Columbia University Vagelos College of Physicians and Surgeons)

  • Hiroshi Mohri

    (Columbia University Vagelos College of Physicians and Surgeons
    Columbia University Vagelos College of Physicians and Surgeons)

  • Bruce Culbertson

    (Columbia University Vagelos College of Physicians and Surgeons
    Columbia University Vagelos College of Physicians and Surgeons)

  • Seo Jung Hong

    (Columbia University Vagelos College of Physicians and Surgeons)

  • Yinkai Duan

    (ShanghaiTech University)

  • Maria I. Luck

    (Columbia University Vagelos College of Physicians and Surgeons
    Columbia University Vagelos College of Physicians and Surgeons)

  • Medini K. Annavajhala

    (Columbia University Vagelos College of Physicians and Surgeons)

  • Yicheng Guo

    (Columbia University Vagelos College of Physicians and Surgeons
    Columbia University Vagelos College of Physicians and Surgeons)

  • Zizhang Sheng

    (Columbia University Vagelos College of Physicians and Surgeons
    Columbia University Vagelos College of Physicians and Surgeons)

  • Anne-Catrin Uhlemann

    (Columbia University Vagelos College of Physicians and Surgeons)

  • Stephen P. Goff

    (Columbia University Vagelos College of Physicians and Surgeons
    Columbia University Vagelos College of Physicians and Surgeons
    Columbia University Vagelos College of Physicians and Surgeons)

  • Yosef Sabo

    (Columbia University Vagelos College of Physicians and Surgeons
    Columbia University Vagelos College of Physicians and Surgeons)

  • Haitao Yang

    (ShanghaiTech University)

  • Alejandro Chavez

    (Columbia University Vagelos College of Physicians and Surgeons)

  • David D. Ho

    (Columbia University Vagelos College of Physicians and Surgeons
    Columbia University Vagelos College of Physicians and Surgeons
    Columbia University Vagelos College of Physicians and Surgeons)

Abstract

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 modalities3–9, 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.

Suggested Citation

  • Sho Iketani & Hiroshi Mohri & Bruce Culbertson & Seo Jung Hong & Yinkai Duan & Maria I. Luck & Medini K. Annavajhala & Yicheng Guo & Zizhang Sheng & Anne-Catrin Uhlemann & Stephen P. Goff & Yosef Sabo, 2023. "Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir," Nature, Nature, vol. 613(7944), pages 558-564, January.
  • Handle: RePEc:nat:nature:v:613:y:2023:i:7944:d:10.1038_s41586-022-05514-2
    DOI: 10.1038/s41586-022-05514-2
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    Citations

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    Cited by:

    1. Maki Kiso & Yuri Furusawa & Ryuta Uraki & Masaki Imai & Seiya Yamayoshi & Yoshihiro Kawaoka, 2023. "In vitro and in vivo characterization of SARS-CoV-2 strains resistant to nirmatrelvir," Nature Communications, Nature, vol. 14(1), pages 1-8, December.
    2. Maki Kiso & Seiya Yamayoshi & Shun Iida & Yuri Furusawa & Yuichiro Hirata & Ryuta Uraki & Masaki Imai & Tadaki Suzuki & Yoshihiro Kawaoka, 2023. "In vitro and in vivo characterization of SARS-CoV-2 resistance to ensitrelvir," Nature Communications, Nature, vol. 14(1), pages 1-8, December.
    3. Haofeng Wang & Qi Yang & Xiaoce Liu & Zili Xu & Maolin Shao & Dongxu Li & Yinkai Duan & Jielin Tang & Xianqiang Yu & Yumin Zhang & Aihua Hao & Yajie Wang & Jie Chen & Chenghao Zhu & Luke Guddat & Hong, 2023. "Structure-based discovery of dual pathway inhibitors for SARS-CoV-2 entry," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. Michael H. J. Rhodin & Archie C. Reyes & Anand Balakrishnan & Nalini Bisht & Nicole M. Kelly & Joyce Sweeney Gibbons & Jonathan Lloyd & Michael Vaine & Tessa Cressey & Miranda Crepeau & Ruichao Shen &, 2024. "The small molecule inhibitor of SARS-CoV-2 3CLpro EDP-235 prevents viral replication and transmission in vivo," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    5. Robert M. Cox & Carolin M. Lieber & Josef D. Wolf & Amirhossein Karimi & Nicole A. P. Lieberman & Zachary M. Sticher & Pavitra Roychoudhury & Meghan K. Andrews & Rebecca E. Krueger & Michael G. Natchu, 2023. "Comparing molnupiravir and nirmatrelvir/ritonavir efficacy and the effects on SARS-CoV-2 transmission in animal models," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    6. Nobuyo Higashi-Kuwata & Kohei Tsuji & Hironori Hayashi & Haydar Bulut & Maki Kiso & Masaki Imai & Hiromi Ogata-Aoki & Takahiro Ishii & Takuya Kobayakawa & Kenta Nakano & Nobutoki Takamune & Naoki Kish, 2023. "Identification of SARS-CoV-2 Mpro inhibitors containing P1’ 4-fluorobenzothiazole moiety highly active against SARS-CoV-2," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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