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The Substitutions L50F, E166A, and L167F in SARS-CoV-2 3CLpro Are Selected by a Protease Inhibitor In Vitro and Confer Resistance To Nirmatrelvir

Jochmans et al., mBio, doi:10.1128/mbio.02815-22
Jan 2023  
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In Vitro study showing that SARS-CoV-2 can develop resistance to 3CLpro inhibitors, including nirmatrelvir (paxlovid), through a combination of 3CLpro mutations (L50F, E166A, L167F). Authors passaged SARS-CoV-2 in the presence of increasing concentrations of the 3CLpro inhibitor ALG-097161, resulting in the stepwise selection of L50F+E166A mutations by passage 8 and the addition of L167F by passage 12. The L50F+E166A+L167F triple mutant virus showed >10-fold increased EC50 values for ALG-097161, nirmatrelvir, PF-00835231, and ensitrelvir compared to wildtype virus. Reverse engineered viruses and a cell-based 3CLpro reporter assay confirmed the roles of these mutations in conferring resistance. Biochemical experiments with recombinant 3CLpro enzymes found the highest levels of resistance (35 to 93-fold increased IC50) for the triple mutant. Structural analysis indicates the mutations reduce inhibitor interactions while maintaining substrate binding. However, the mutations are associated with reduced intrinsic 3CLpro enzymatic activity, suggesting a potential fitness cost for the virus.
Jochmans et al., 10 Jan 2023, peer-reviewed, 25 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperPaxlovidAll
The Substitutions L50F, E166A, and L167F in SARS-CoV-2 3CLpro Are Selected by a Protease Inhibitor In Vitro and Confer Resistance To Nirmatrelvir
Dirk Jochmans, Cheng Liu, Kim Donckers, Antitsa Stoycheva, Sandro Boland, Sarah K Stevens, Chloe De Vita, Bert Vanmechelen, Piet Maes, Bettina Trüeb, Nadine Ebert, Volker Thiel, Steven De Jonghe, Laura Vangeel, Dorothée Bardiot, Andreas Jekle, Lawrence M Blatt, Leonid Beigelman, Julian A Symons, Pierre Raboisson, Patrick Chaltin, Arnaud Marchand, Johan Neyts, Jerome Deval, Koen Vandyck
mBio, doi:10.1128/mbio.02815-22
The SARS-CoV-2 main protease (3CLpro) has an indispensable role in the viral life cycle and is a therapeutic target for the treatment of COVID-19. The potential of 3CLpro-inhibitors to select for drug-resistant variants needs to be established. Therefore, SARS-CoV-2 was passaged in vitro in the presence of increasing concentrations of ALG-097161, a probe compound designed in the context of a 3CLpro drug discovery program. We identified a combination of amino acid substitutions in 3CLpro (L50F E166A L167F) that is associated with a >20Â increase in 50% effective concentration (EC 50 ) values for ALG-097161, nirmatrelvir (PF-07321332), PF-00835231, and ensitrelvir. While two of the single substitutions (E166A and L167F) provide low-level resistance to the inhibitors in a biochemical assay, the triple mutant results in the highest levels of resistance (6Â to 72Â). All substitutions are associated with a significant loss of enzymatic 3CLpro activity, suggesting a reduction in viral fitness. Structural biology analysis indicates that the different substitutions reduce the number of inhibitor/enzyme interactions while the binding of the substrate is maintained. These observations will be important for the interpretation of resistance development to 3CLpro inhibitors in the clinical setting. IMPORTANCE Paxlovid is the first oral antiviral approved for treatment of SARS-CoV-2 infection. Antiviral treatments are often associated with the development of drugresistant viruses. In order to guide the use of novel antivirals, it is essential to understand the risk of resistance development and to characterize the associated changes in the viral genes and proteins. In this work, we describe for the first time a pathway that allows SARS-CoV-2 to develop resistance against Paxlovid in vitro. The characteristics of in vitro antiviral resistance development may be predictive for the clinical situation. Therefore, our work will be important for the management of COVID-19 with Paxlovid and next-generation SARS-CoV-2 3CLpro inhibitors.
References
Abdelnabi, Foo, Jochmans, Vangeel, Jonghe et al., The oral protease inhibitor (PF-07321332) protects Syrian hamsters against infection with SARS-CoV-2 variants of concern, Nat, doi:10.1038/s41467-022-28354-0
Andreano, Piccini, Licastro, Casalino, Johnson et al., SARS-CoV-2 escape from a highly neutralizing COVID-19 convalescent plasma, Proc Natl Acad Sci U S A, doi:10.1073/pnas.2103154118
Arnold, Profile of PBI-0451 an orally administered 3CL protease inhibitor of SARS-CoV-2 for COVID-19. ICAR2022 meeting
Boras, Jones, Anson, Arenson, Aschenbrenner et al., Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19, Nat Commun, doi:10.1038/s41467-021-26239-2
Boudewijns, Thibaut, Kaptein, Li, Vergote et al., SARS-CoV-2 3CLpro Inhibitor Resistance Development, mBio Month YYYY
Fan, Ma, Han, Liang, Wei et al., The substrate specificity of SARS coronavirus 3C-like proteinase, Biochem Biophys Res Commun, doi:10.1016/j.bbrc.2005.02.061
Flynn, Samant, Schneider-Nachum, Barkan, Yilmaz et al., Comprehensive fitness landscape of SARS-CoV-2 Mpro reveals insights into viral resistance mechanisms, Elife, doi:10.7554/eLife.77433
Focosi, Maggi, Mcconnell, Casadevall, Very low levels of remdesivir resistance in SARS-COV-2 genomes after 18 months of massive usage during the COVID19 pandemic: A GISAID exploratory analysis, Antiviral Res, doi:10.1016/j.antiviral.2022.105247
Guo, Wu, Zhang, Liu, Li et al., Transmitted drug resistance in antiretroviral therapy-naive persons with acute/early/primary HIV infection: a systematic review and meta-analysis, Front Pharmacol, doi:10.3389/fphar.2021.718763
Gurard-Levin, Liu, Jekle, Jaisinghani, Ren et al., Evaluation of SARS-CoV-2 3C-like protease inhibitors using self-assembled monolayer desorption ionization mass spectrometry, Antiviral Res, doi:10.1016/j.antiviral.2020.104924
Hammond, Leister-Tebbe, Gardner, Abreu, Wisemandle et al., Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19, N Engl J Med, doi:10.1056/NEJMoa2118542
He, Zhang, Yan, Xu, Xie et al., Distribution and evolution of H1N1 influenza A viruses with adamantanes-resistant mutations worldwide from 1918 to 2019, J Med Virol, doi:10.1002/jmv.26670
Heilmann, Costacurta, Moghadasi, Ye, Pavan et al., SARS-CoV-2 3CL(pro) mutations selected in a VSV-based system confer resistance to nirmatrelvir, ensitrelvir, and GC376, Sci Transl Med, doi:10.1126/scitranslmed.abq7360
Hoffman, Kania, Brothers, Davies, Ferre et al., Discovery of ketone-based covalent inhibitors of coronavirus 3CL proteases for the potential therapeutic treatment of COVID-19, J Med Chem, doi:10.1021/acs.jmedchem.0c01063
Hogan, Duerr, Dimartino, Marier, Hochman et al., Remdesivir resistance in transplant recipients with persistent coronavirus disease 2019 (COVID-19), Clin Infect Dis, doi:10.1093/cid/ciac769
Iketani, Mohri, Culbertson, Hong, Duan et al., Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir, Nature, doi:10.1038/s41586-022-05514-2
Ison, Hayden, Hay, Gubareva, Govorkova et al., Influenza polymerase inhibitor resistance: Assessment of the current state of the art: a report of the isirv Antiviral group, Antiviral Res, doi:10.1016/j.antiviral.2021.105158
Jochmans, Leyssen, Neyts, A novel method for high-throughput screening to quantify antiviral activity against viruses that induce limited CPE, J Virol Methods, doi:10.1016/j.jviromet.2012.04.011
Lee, Yang, Gribenko, Perrin, Zhu et al., Genetic surveillance of SARS-CoV-2 M(pro) reveals high sequence and structural conservation prior to the introduction of protease inhibitor Paxlovid, mBio, doi:10.1128/mbio.00869-22
Liu, Boland, Scholle, Bardiot, Marchand et al., Dual inhibition of SARS-CoV-2 and human rhinovirus with protease inhibitors in clinical development, Antiviral Res, doi:10.1016/j.antiviral.2021.105020
Matthijnssens, Van Ranst, Compernolle, Schramm, Van Laere et al., STAT2 signaling restricts viral dissemination but drives severe pneumonia in SARS-CoV-2 infected hamsters, Nat Commun, doi:10.1038/s41467-020-19684-y
Menéndez-Arias, Delgado, Update and latest advances in antiretroviral therapy, Trends Pharmacol Sci, doi:10.1016/j.tips.2021.10.004
Moghadasi, Esler, Otsuka, Becker, Moraes et al., Gain-of-signal assays for probing inhibition of SARS-CoV-2 M(pro)/3CL(pro) in living cells, mBio, doi:10.1128/mbio.00784-22
Mukae, Yotsuyanagi, Ohmagari, Doi, Imamura et al., A randomized phase 2/3 study of ensitrelvir, a novel oral SARS-CoV-2 3C-like protease inhibitor, in Japanese patients with mild-to-moderate COVID-19 or asymptomatic SARS-CoV-2 infection: results of the phase 2a part, Antimicrob Agents Chemother, doi:10.1128/aac.00697-22
Nhu, Labroussaa, Ebert, V'kovski, Stalder et al., Rapid reconstruction of SARS-CoV-2 using a synthetic genomics platform, Nature, doi:10.1038/s41586-020-2294-9
Owen, Allerton, Anderson, Aschenbrenner, Avery et al., An oral SARS-CoV-2 M(pro) inhibitor clinical candidate for the treatment of COVID-19, Science, doi:10.1126/science.abl4784
Reis, Metzendorf, Kuehn, Popp, Gagyor et al., Nirmatrelvir combined with ritonavir for preventing and treating COVID-19, Cochrane Database Syst Rev, doi:10.1002/14651858.CD015395.pub2
Stevens, Pruijssers, Lee, Gordon, Tchesnokov et al., Mutations in the SARS-CoV-2 RNA-dependent RNA polymerase confer resistance to remdesivir by distinct mechanisms, Sci Transl Med, doi:10.1126/scitranslmed.abo0718
Taylor, Pfizer, in a rare COVID-19 setback, dumps Paxlovid's intravenous sibling in further blow to ACTIV-3
Tomar, Johnston, John, Osswald, Nyalapatla et al., Ligand-induced dimerization of Middle East respiratory syndrome (MERS) coronavirus nsp5 protease (3CLpro): implications for nsp5 regulation and the development of antivirals, J Biol Chem, doi:10.1074/jbc.M115.651463
Ullrich, Nitsche, The SARS-CoV-2 main protease as drug target, Bioorg Med Chem Lett, doi:10.1016/j.bmcl.2020.127377
Unoh, Uehara, Nakahara, Nobori, Yamatsu et al., Discovery of S-217622, a noncovalent oral SARS-CoV-2 3CL protease inhibitor clinical candidate for treating COVID-19, J Med Chem, doi:10.1021/acs.jmedchem.2c00117
Vandyck, Deval, Considerations for the discovery and development of 3-chymotrypsin-like cysteine protease inhibitors targeting SARS-CoV-2 infection, Curr Opin Virol, doi:10.1016/j.coviro.2021.04.006
Vangeel, Chiu, Jonghe, Maes, Slechten et al., Remdesivir, molnupiravir and SARS-CoV-2 3CLpro Inhibitor Resistance Development, mBio Month YYYY
Wen, Chen, Tang, Wang, Zhou et al., Efficacy and safety of three new oral antiviral treatment (molnupiravir, fluvoxamine and Paxlovid) for COVID-19: a meta-analysis, Ann Med, doi:10.1080/07853890.2022.2034936
Wong, Au, Lau, Lau, Cowling et al., Realworld effectiveness of early molnupiravir or nirmatrelvir-ritonavir in hospitalised patients with COVID-19 without supplemental oxygen requirement on admission during Hong Kong's Omicron BA.2 wave: a retrospective cohort study, Lancet Infect Dis, doi:10.1016/S1473-3099(22)00507-2
Xiong, Su, Zhao, Xie, Shao et al., What coronavirus 3C-like protease tells us: from structure, substrate selectivity, to inhibitor design, Med Res Rev, doi:10.1002/med.21783
Zephyr, Yilmaz, Schiffer, Viral proteases: structure, mechanism and inhibition, Enzymes, doi:10.1016/bs.enz.2021.09.004
Zhou, Gammeltoft, Ryberg, Pham, Fahnøe et al., with high fitness in vitro, doi:10.1101/2022.06.06.494921
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Nirmatrelvir resistant SARS-CoV-2 variants with high ' 'fitness in vitro. bioRxiv. doi:10.1101/2022.06.06.494921.', 'DOI': '10.1101/2022.06.06.494921'}, { 'key': 'e_1_3_2_36_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1126/scitranslmed.abq7360'}, {'key': 'e_1_3_2_37_2', 'doi-asserted-by': 'publisher', 'DOI': '10.7554/eLife.77433'}, {'key': 'e_1_3_2_38_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41467-020-19684-y'}, { 'key': 'e_1_3_2_39_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.antiviral.2021.105020'}, { 'key': 'e_1_3_2_40_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.jviromet.2012.04.011'}], 'container-title': 'mBio', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://journals.asm.org/doi/pdf/10.1128/mbio.02815-22', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://journals.asm.org/doi/pdf/10.1128/mbio.02815-22', 'content-type': 'unspecified', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2023, 1, 10]], 'date-time': '2023-01-10T14:21:40Z', 'timestamp': 1673360500000}, 'score': 1, 'resource': {'primary': {'URL': 'https://journals.asm.org/doi/10.1128/mbio.02815-22'}}, 'subtitle': [], 'editor': [{'given': 'Peter', 'family': 'Palese', 'sequence': 'additional', 'affiliation': []}], 'short-title': [], 'issued': {'date-parts': [[2023, 1, 10]]}, 'references-count': 39, 'alternative-id': ['10.1128/mbio.02815-22'], 'URL': 'http://dx.doi.org/10.1128/mbio.02815-22', 'relation': {}, 'ISSN': ['2150-7511'], 'subject': ['Virology', 'Microbiology'], 'container-title-short': 'mBio', 'published': {'date-parts': [[2023, 1, 10]]}, 'assertion': [ { 'value': '2022-10-07', 'order': 0, 'name': 'received', 'label': 'Received', 'group': {'name': 'publication_history', 'label': 'Publication History'}}, { 'value': '2022-12-06', 'order': 1, 'name': 'accepted', 'label': 'Accepted', 'group': {'name': 'publication_history', 'label': 'Publication History'}}, { 'value': '2023-01-10', 'order': 2, 'name': 'published', 'label': 'Published', 'group': {'name': 'publication_history', 'label': 'Publication History'}}]}
Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.
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