Journal article
Molecular mechanisms of SARS-CoV-2 resistance to nirmatrelvir
Nature (London), Vol.622(7982), pp.376-382
10/12/2023
DOI: 10.1038/s41586-023-06609-0
PMID: 37696289
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.
A biochemical and structural analysis demonstrates that alterations at the substrate-binding pocket of the main protease of SARS-CoV-2 can allow the virus to develop resistance to nirmatrelvir in two distinct ways.
Details
- Title: Subtitle
- Molecular mechanisms of SARS-CoV-2 resistance to nirmatrelvir
- Creators
- Yinkai Duan - ShanghaiTech UniversityHao Zhou - ShanghaiTech UniversityXiang Liu - Nankai UniversitySho Iketani - Aaron Diamond AIDS Research CenterMengmeng Lin - ShanghaiTech UniversityXiaoyu Zhang - ShanghaiTech UniversityQucheng Bian - ShanghaiTech UniversityHaofeng Wang - ShanghaiTech UniversityHaoran Sun - ShanghaiTech UniversitySeo Jung Hong - Columbia UniversityBruce Culbertson - Columbia UniversityHiroshi Mohri - Aaron Diamond AIDS Research CenterMaria I. Luck - Columbia UniversityYan Zhu - ShanghaiTech UniversityXiaoce Liu - Shanghai Clinical Research CenterYuchi Lu - Shanghai Clinical Research CenterXiuna Yang - ShanghaiTech UniversityKailin Yang - Cleveland ClinicYosef Sabo - Aaron Diamond AIDS Research CenterAlejandro Chavez - Columbia UniversityStephen P. Goff - Aaron Diamond AIDS Research CenterZihe Rao - ShanghaiTech UniversityDavid D. Ho - Aaron Diamond AIDS Research CenterHaitao Yang - Shanghai Clinical Research Center
- Resource Type
- Journal article
- Publication Details
- Nature (London), Vol.622(7982), pp.376-382
- Publisher
- NATURE PORTFOLIO
- DOI
- 10.1038/s41586-023-06609-0
- PMID
- 37696289
- ISSN
- 0028-0836
- eISSN
- 1476-4687
- Number of pages
- 7
- Grant note
- Discovery Technology Platform of the Shanghai Institute for Advanced Immunochemical Studies National Natural Science Foundation of China; National Natural Science Foundation of China (NSFC) Career Award for Medical Scientists from the Burroughs Wellcome Fund; Burroughs Wellcome Fund We acknowledge the Discovery Technology Platform of the Shanghai Institute for Advanced Immunochemical Studies and the Molecular and Cell Biology Core Facility of the School of Life Science and Technology, ShanghaiTech University for use of their instrumen YDZX20213100001556; 20XD1422900 / Guangzhou Laboratory 92169109 / Science and Technology Commission of Shanghai Municipality; Science & Technology Commission of Shanghai Municipality (STCSM) Shanghai Frontiers Science Center for Biomacromolecules and Precision Medicine of ShanghaiTech University SRPG22-003; SRPG22-011 / ShanghaiTech University
- Language
- English
- Date published
- 10/12/2023
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984696707602771
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