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Functional and structural characterization of treatment-emergent nirmatrelvir resistance mutations at low frequencies in the main protease (Mpro) reveals a unique evolutionary route for SARS-CoV-2 to gain resistance

Deschenes et al., The Journal of Infectious Diseases, doi:10.1093/infdis/jiaf294, Jun 2025
https://c19early.org/deschenes.html
In Vitro and In Silico study showing that novel SARS-CoV-2 main protease (Mpro) mutations confer resistance to paxlovid. Authors identified new Mpro clinical variants, including D48D/L58F/P132H and D48D/L67V/K90R/P132H, in patients who remained SARS-CoV-2 positive after paxlovid treatment. Experiments in Caco-2 cells revealed these mutations, distant from the Mpro active site, led to significant nirmatrelvir and C5a resistance while retaining the enzyme's activity.
Deschenes et al., 3 Jun 2025, Canada, peer-reviewed, 25 authors, study period February 2022 - July 2023. Contact: rkozak@shn.ca, fjean@mail.ubc.ca.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
Functional and Structural Characterization of Treatment-Emergent Nirmatrelvir Resistance Mutations at Low Frequencies in the Main Protease (Mpro) Reveals a Unique Evolutionary Route for SARS-CoV-2 to Gain Resistance
Natalie M Deschenes, Jimena Pérez-Vargas, Zoe Zhong, Merrilee Thomas, Calem Kenward, Wesley A Mosimann, Liam J Worrall, Nicholas Waglechner, Angel Xinliu Li, Finlay Maguire, Patryk Aftanas, Jason R Smith, Jared Lim, Robert N Young, Artem Cherkasov, Lubna Farooqi, Adnan Moinuddin, Lina Siddiqi, Imaan Malik, Maxime Lefebvre, Mark Paetzel, Natalie C J Strynadka, Dr François Jean, Allison Mcgeer, Dr Robert A Kozak
The Journal of Infectious Diseases, doi:10.1093/infdis/jiaf294
Background: The main protease (M pro ) is one of the most attractive targets for antiviral drug discovery against SARS-CoV-2. Mutations in M pro have been linked to resistance against nirmatrelvir-ritonavir (NIR-RIT), an important therapy for SARS-CoV-2 infection. This study aimed to identify low-frequency antiviral resistance mutations in M pro from NIR-RIT-treated patients and to analyze the enzymatic properties, inhibitor susceptibility, and structural features of new M pro clinical variants. Methods: We screened 1,528 SARS-CoV-2-positive patients from two hospitals and identified 17 who remained positive after treatment. Whole genome sequencing of nasopharyngeal specimens was conducted to identify M pro clinical variants. The impact of these mutations on M pro activity and inhibitor susceptibility was investigated using a fluorescent enzymatic biosensor in human cells, along with in vitro thermal stability and structure-based analyses of the M pro mutants and M pro -NIR complexes. Results: The analysis identified two novel M pro clinical variants: D48D/L58F/P132H (variant 1) and D48D/L67V/K90R/P132H (variant 2). Our data show that the selected clinical mutations are localized in the M pro N-terminal domain, are far from the catalytic site, and strongly impact NIR resistance without affecting M pro activity. Structural analysis and thermal denaturation analyses revealed that these mutations may disrupt the substrate binding site's structure and dynamics, reducing protein stability and potentially impacting substrate binding or dimerization without compromising catalytic activity. Conclusions: Our new M pro clinical mutations that confer complete resistance to NIR were not identified during previous cell-culture-based studies. More research is needed to explore resistance mechanisms, providing insights into strategies that mitigate resistance and protect therapeutic efficacy.
Author Contributions Conceptualization: FJ, AM, RAK Methodology, Investigation: patient collection samples -ZZ, LF, AM, LS, IM, MF, ALX; chart review -ZZ, LF, AM, LS, IM, MF, ALX; sequencing-NMD, PA; data analysis -NW, FM; cellular enzymatic assays -JPV, MT, FJ; materials for enzymatic assay -JRS, RNY, AC; M pro cloning, protein production for crystallography, crystallographic data collection, data processing, structure refinement -CK, WAM, LJW, JL, MP, NCJS; M pro inhibitor C5a: JRS, RNY, AC; Writing: original draft: NMD, cellular enzymatic assays -JPV, FJ; crystallography -CK, LJW, NCJS; review and editing -NMD, JPV, FJ, AM, RAK with input from all authors. All authors reviewed the final manuscript.
References
Abramson, Adler, Dunger, Evans, Green et al., Accurate structure prediction of biomolecular interactions with AlphaFold 3, Nature
Afonine, Poon, Read, Sobolev, Terwilliger et al., Real-space refinement in PHENIX for cryo-EM and crystallography, Acta Cryst D
Agirre, Atanasova, Bagdonas, Ballard, Baslé et al., The CCP4 suite: integrative software for macromolecular crystallography, Acta Cryst D
Almalki, Izhari, Alyahyawi, Alatawi, Klufah et al., Mutational Analysis of Circulating Omicron SARS-CoV-2 Lineages in the Al-Baha Region of Saudi Arabia, J Multidiscip Healthc
Arbel, Sagy, Hoshen, Battat, Lavie et al., Nirmatrelvir Use and Severe Covid-19 Outcomes during the Omicron Surge, N Engl J Med
Bloom, Beichman, Neher, Harris, Evolution of the SARS-CoV-2 Mutational Spectrum, Molecular Biology and Evolution
Duan, Zhou, Liu, Iketani, Lin et al., Molecular mechanisms of SARS-CoV-2 resistance to nirmatrelvir, Nature
Garcia-Segura, Llop-Peiró, Novau-Ferré, Mestres-Truyol, Saldivar-Espinoza et al., SARS-CoV-2 main protease (M-pro) mutational profiling: An insight into mutation coldspots, Computers in Biology and Medicine
Garrison, Marth, Haplotype-based variant detection from short-read sequencing
Hammond, Leister-Tebbe, Gardner, Abreu, Wisemandle, Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19, N Engl J Med
Hermankova, Ray, Ruff, Powell-Davis, Ingersoll et al., HIV-1 drug resistance profiles in children and adults with viral load of <50 copies/ml receiving combination therapy, JAMA
Hirotsu, Kobayashi, Kakizaki, Saito, Tsutsui et al., Multidrug-resistant mutations to antiviral and antibody therapy in an immunocompromised patient infected with SARS-CoV-2, Med
Hu, Lewandowski, Tan, Zhang, Morgan et al., Naturally Occurring Mutations of SARS-CoV-2 Main Protease Confer Drug Resistance to Nirmatrelvir, ACS Cent Sci
Iketani, Mohri, Culbertson, Hong, Duan et al., Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir, bioRxiv
Ji, Kozak, Biondi, Pilon, Vallee et al., Next generation sequencing of the hepatitis C virus NS5B gene reveals potential novel S282 drug resistance mutations, Virology
Jin, Du, Xu, Deng, Liu et al., Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors, Nature
Jochmans, Liu, Donckers, Stoycheva, Boland et al., The Substitutions L50F, E166A, and L167F in SARS-CoV-2 3CLpro Are Selected by a Protease Inhibitor In Vitro and Confer Resistance To Nirmatrelvir, mBio
Kim, Calabrese, Wang, Qin, Rao et al., The roles of APOBEC-mediated RNA editing in SARS-CoV-2 mutations, replication and fitness, Sci Rep
Kneller, Phillips, Neill, Jedrzejczak, Stols et al., Structural plasticity of SARS-CoV-2 3CL Mpro active site cavity revealed by room temperature X-ray crystallography, Nat Commun
Lee, Kenward, Worrall, Vuckovic, Gentile et al., X-ray crystallographic characterization of the SARS-CoV-2 main protease polyprotein cleavage sites essential for viral processing and maturation, Nat Commun
Lee, Worrall, Vuckovic, Rosell, Gentile et al., Crystallographic structure of wild-type SARS-CoV-2 main protease acyl-enzyme intermediate with physiological C-terminal autoprocessing site, Nat Commun
Lee, Yang, Gribenko, Perrin, Zhu et al., Genetic Surveillance of SARS-CoV-2 Mpro Reveals High Sequence and Structural Conservation Prior to the Introduction of Protease Inhibitor Paxlovid, mBio
Lewnard, Mclaughlin, Malden, Hong, Puzniak et al., Effectiveness of nirmatrelvir-ritonavir in preventing hospital admissions and deaths in people with COVID-19: a cohort study in a large US health-care system, The Lancet Infectious Diseases
Lima, Gill, Yip, Hogg, Montaner et al., Increased resilience to the development of drug resistance with modern boosted protease inhibitor-based highly active antiretroviral therapy, J Infect Dis
Matyášek, Kovařík, Mutation Patterns of Human SARS-CoV-2 and Bat RaTG13 Coronavirus Genomes Are Strongly Biased Towards C>U Transitions, Indicating Rapid Evolution in Their Hosts, Genes
Mody, Ho, Wills, Mawri, Lawson et al., Identification of 3 -chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents, Commun Biol
Moghadasi, Heilmann, Khalil, Nnabuife, Kearns et al., Transmissible SARS-CoV-2 variants with resistance to clinical protease inhibitors, Science Advances
Nasir, Kozak, Aftanas, Raphenya, Smith et al., A Comparison of Whole Genome Sequencing of SARS-CoV-2 Using Amplicon-Based Sequencing, Random Hexamers, and Bait Capture, Viruses
Owen, Allerton, Anderson, Aschenbrenner, Avery et al., An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19, Science
Pettersen, Goddard, Huang, Meng, Couch et al., UCSF ChimeraX: Structure visualization for researchers, educators, and developers, Protein Sci
Pérez-Vargas, Worrall, Olmstead, Ton, Lee et al., A novel class of broad-spectrum active-site-directed 3C-like protease inhibitors with nanomolar antiviral activity against highly immune-evasive SARS-CoV-2 Omicron subvariants, Emerg Microbes Infect
Rosa, Dantas, Do Nascimento, Da Silva, De Oliveira et al., In Vitro and In Vivo Models for Studying SARS-CoV-2, the Etiological Agent Responsible for COVID-19 Pandemic, Viruses
Sacco, Hu, Gongora, Meilleur, Kemp et al., The P132H mutation in the main protease of Omicron SARS-CoV-2 decreases thermal stability without compromising catalysis or small-molecule drug inhibition, Cell Res
Senisterra, Markin, Yamazaki, Hui, Vedadi et al., Screening for ligands using a generic and high-throughput light-scattering-based assay, J Biomol Screen
Simmonds, Rampant C→U Hypermutation in the Genomes of SARS-CoV-2 and Other Coronaviruses: Causes and Consequences for Their Short-and Long-Term Evolutionary Trajectories, mSphere
Simpson, jts/ncov-tools
Sjaarda, Lau, Simpson, Fattouh, Biondi et al., Prevalence of Low -Frequency, Antiviral Resistance Variants in SARS-CoV-2 Isolates in Ontario, Canada, 2020-2023, JAMA Netw Open
Ullrich, Ekanayake, Otting, Nitsche, Main protease mutants of SARS-CoV-2 variants remain susceptible to nirmatrelvir, Bioorganic & Medicinal Chemistry Letters
Wang, Xie, Yu, Dong, Li, Enhancing the understandings on SARS-CoV-2 main protease (Mpro) from molecular dynamics and machine learning, International Journal of Biological Macromolecules
Wyles, Dvory-Sobol, Svarovskaia, Doehle, Martin et al., Post-treatment resistance analysis of hepatitis C virus from phase II and III clinical trials of ledipasvir/sofosbuvir, J Hepatol
Xie, Choi, Al-Aly, Association of Treatment With Nirmatrelvir and the Risk of Post-COVID-19 Condition, JAMA Intern Med
Yashvardhini, Kumar, Jha, Analysis of SARS-CoV-2 mutations in the main viral protease (NSP5) and its implications on the vaccine designing strategies, Vacunas
Zhang, Lin, Sun, Curth, Drosten et al., Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors, Science
Zhou, Gammeltoft, Ryberg, Tjørnelund, Binderup, Nirmatrelvirresistant SARS-CoV-2 variants with high fitness in an infectious cell culture system, Science Advances
Zhu, Yurgelonis, Yang, Guan, Li, In vitro selection and analysis of SARS-CoV-2 nirmatrelvir resistance mutations contributing to clinical virus resistance surveillance, Sci Adv
Zuckerman, Bucris, Keidar-Friedman, Amsalem, Brosh-Nissimov, Nirmatrelvir Resistance-de Novo E166V/L50V Mutations in an Immunocompromised Patient Treated With Prolonged Nirmatrelvir/Ritonavir Monotherapy Leading to Clinical and Virological Treatment Failure-a Case Report, Clin Infect Dis
DOI record: { "DOI": "10.1093/infdis/jiaf294", "ISSN": [ "0022-1899", "1537-6613" ], "URL": "http://dx.doi.org/10.1093/infdis/jiaf294", "abstract": "<jats:title>Abstract</jats:title>\n <jats:sec>\n <jats:title>Background</jats:title>\n <jats:p>The main protease (Mpro) is one of the most attractive targets for antiviral drug discovery against SARS-CoV-2. Mutations in Mpro have been linked to resistance against nirmatrelvir-ritonavir (NIR-RIT), an important therapy for SARS-CoV-2 infection. This study aimed to identify low-frequency antiviral resistance mutations in Mpro from NIR-RIT-treated patients and to analyze the enzymatic properties, inhibitor susceptibility, and structural features of new Mpro clinical variants.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Methods</jats:title>\n <jats:p>We screened 1,528 SARS-CoV-2-positive patients from two hospitals and identified 17 who remained positive after treatment. Whole genome sequencing of nasopharyngeal specimens was conducted to identify Mpro clinical variants. The impact of these mutations on Mpro activity and inhibitor susceptibility was investigated using a fluorescent enzymatic biosensor in human cells, along with in vitro thermal stability and structure-based analyses of the Mpro mutants and Mpro-NIR complexes.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Results</jats:title>\n <jats:p>The analysis identified two novel Mpro clinical variants: D48D/L58F/P132H (variant 1) and D48D/L67V/K90R/P132H (variant 2). Our data show that the selected clinical mutations are localized in the Mpro N-terminal domain, are far from the catalytic site, and strongly impact NIR resistance without affecting Mpro activity. Structural analysis and thermal denaturation analyses revealed that these mutations may disrupt the substrate binding site's structure and dynamics, reducing protein stability and potentially impacting substrate binding or dimerization without compromising catalytic activity.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Conclusions</jats:title>\n <jats:p>Our new Mpro clinical mutations that confer complete resistance to NIR were not identified during previous cell-culture-based studies. More research is needed to explore resistance mechanisms, providing insights into strategies that mitigate resistance and protect therapeutic efficacy.</jats:p>\n </jats:sec>", "author": [ { "affiliation": [ { "name": "Biological Sciences Platform, Sunnybrook Research Institute , Toronto, ON ,", "place": [ "Canada" ] } ], "family": "Deschenes", "given": "Natalie M", "sequence": "first" }, { "ORCID": "https://orcid.org/0000-0002-4337-7903", "affiliation": [ { "name": "Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia , Vancouver ,", "place": [ "Canada" ] } ], "authenticated-orcid": false, "family": "Pérez-Vargas", "given": "Jimena", "sequence": "additional" }, { "affiliation": [ { "name": "Sinai Health System, Mount Sinai Hospital , Toronto, ON  ", "place": [ "Canada" ] } ], "family": "Zhong", "given": "Zoe", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0002-3430-0912", "affiliation": [ { "name": "Montana Molecular , 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{ "name": "Department of Chemistry, Simon Fraser University , Burnaby, BC ,", "place": [ "Canada" ] } ], "authenticated-orcid": false, "family": "Smith", "given": "Jason R", "sequence": "additional" }, { "ORCID": "https://orcid.org/0009-0009-2640-033X", "affiliation": [ { "name": "Department of Molecular Biology and Biochemistry, Simon Fraser University , Burnaby, British Columbia ,", "place": [ "Canada" ] } ], "authenticated-orcid": false, "family": "Lim", "given": "Jared", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Chemistry, Simon Fraser University , Burnaby, BC ,", "place": [ "Canada" ] } ], "family": "Young", "given": "Robert N", "sequence": "additional" }, { "affiliation": [ { "name": "Vancouver Prostate Centre, University of British Columbia , Vancouver, BC ,", "place": [ "Canada" ] } ], "family": "Cherkasov", "given": "Artem", "sequence": "additional" }, { "affiliation": [ { "name": "Sinai Health System, Mount Sinai Hospital , Toronto, ON  ", 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