Molecular mechanisms of SARS-CoV-2 resistance to nirmatrelvir

Yinkai Duan, Hao Zhou, Xiang Liu, Sho Iketani, Mengmeng Lin, Xiaoyu Zhang, Qucheng Bian, Haofeng Wang, Haoran Sun, Seo Jung Hong, Bruce Culbertson, Hiroshi Mohri, Maria I. Luck, Yan Zhu, Xiaoce Liu, Yuchi Lu, Xiuna Yang, Kailin Yang, Yosef Sabo, Alejandro Chavez, Stephen P. Goff, Zihe Rao, David D. Ho () and Haitao Yang ()
Additional contact information
Yinkai Duan: ShanghaiTech University
Hao Zhou: ShanghaiTech University
Xiang Liu: Nankai University
Sho Iketani: Columbia University Vagelos College of Physicians and Surgeons
Mengmeng Lin: ShanghaiTech University
Xiaoyu Zhang: ShanghaiTech University
Qucheng Bian: ShanghaiTech University
Haofeng Wang: ShanghaiTech University
Haoran Sun: ShanghaiTech University
Seo Jung Hong: Columbia University Vagelos College of Physicians and Surgeons
Bruce Culbertson: Columbia University Vagelos College of Physicians and Surgeons
Hiroshi Mohri: Columbia University Vagelos College of Physicians and Surgeons
Maria I. Luck: Columbia University Vagelos College of Physicians and Surgeons
Yan Zhu: ShanghaiTech University
Xiaoce Liu: ShanghaiTech University
Yuchi Lu: ShanghaiTech University
Xiuna Yang: ShanghaiTech University
Kailin Yang: Cleveland Clinic
Yosef Sabo: Columbia University Vagelos College of Physicians and Surgeons
Alejandro Chavez: Columbia University Vagelos College of Physicians and Surgeons
Stephen P. Goff: Columbia University Vagelos College of Physicians and Surgeons
Zihe Rao: ShanghaiTech University
David D. Ho: Columbia University Vagelos College of Physicians and Surgeons
Haitao Yang: ShanghaiTech University

Nature, 2023, vol. 622, issue 7982, 376-382

Abstract: Abstract Nirmatrelvir is a specific antiviral drug that targets the main protease (Mpro) of SARS-CoV-2 and has been approved to treat COVID-191,2. As an RNA virus characterized by high mutation rates, whether SARS-CoV-2 will develop resistance to nirmatrelvir is a question of concern. Our previous studies have shown that several mutational pathways confer resistance to nirmatrelvir, but some result in a loss of viral replicative fitness, which is then compensated for by additional alterations3. The molecular mechanisms for this observed resistance are unknown. Here we combined biochemical and structural methods to demonstrate that alterations at the substrate-binding pocket of Mpro can allow SARS-CoV-2 to develop resistance to nirmatrelvir in two distinct ways. Comprehensive studies of the structures of 14 Mpro mutants in complex with drugs or substrate revealed that alterations at the S1 and S4 subsites substantially decreased the level of inhibitor binding, whereas alterations at the S2 and S4′ subsites unexpectedly increased protease activity. Both mechanisms contributed to nirmatrelvir resistance, with the latter compensating for the loss in enzymatic activity of the former, which in turn accounted for the restoration of viral replicative fitness, as observed previously3. Such a profile was also observed for ensitrelvir, another clinically relevant Mpro inhibitor. These results shed light on the mechanisms by which SARS-CoV-2 evolves to develop resistance to the current generation of protease inhibitors and provide the basis for the design of next-generation Mpro inhibitors.

Date: 2023
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DOI: 10.1038/s41586-023-06609-0

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