Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir

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, Haitao Yang, Alejandro Chavez () and David D. Ho ()
Additional contact information
Sho Iketani: Columbia University Vagelos College of Physicians and Surgeons
Hiroshi Mohri: Columbia University Vagelos College of Physicians and Surgeons
Bruce Culbertson: 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
Medini K. Annavajhala: Columbia University Vagelos College of Physicians and Surgeons
Yicheng Guo: Columbia University Vagelos College of Physicians and Surgeons
Zizhang Sheng: 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
Yosef Sabo: 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

Nature, 2023, vol. 613, issue 7944, 558-564

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-022-05514-2

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