No retraction, correction or concern found when last checked on Oct 21, 2026.

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 and 22 more

mBio · 2023 · CC BY

Abstract

Paxlovid is the first oral antiviral approved for treatment of SARS-CoV-2 infection. Antiviral treatments are often associated with the development of drug-resistant viruses.

References 39

1.
Xiong M, Su H, Zhao W, Xie H, Shao Q, Xu Y. 2021. What coronavirus 3C-like protease tells us: from structure, substrate selectivity, to inhibitor design. Med Res Rev 41:1965–1998. doi:.
Not in our library10.1002/med.21783
2.
Fan K, Ma L, Han X, Liang H, Wei P, Liu Y, Lai L. 2005. The substrate specificity of SARS coronavirus 3C-like proteinase. Biochem Biophys Res Commun 329:934–940. doi:.
Not in our library10.1016/j.bbrc.2005.02.061
3.
Ullrich S, Nitsche C. 2020. The SARS-CoV-2 main protease as drug target. Bioorg Med Chem Lett 30:127377. doi:.
Not in our library10.1016/j.bmcl.2020.127377
4.
Vandyck K, Deval J. 2021. Considerations for the discovery and development of 3-chymotrypsin-like cysteine protease inhibitors targeting SARS-CoV-2 infection. Curr Opin Virol 49:36–40. doi:.
Not in our library10.1016/j.coviro.2021.04.006
5.
Owen DR, Allerton CMN, Anderson AS, Aschenbrenner L, Avery M, Berritt S, Boras B, Cardin RD, Carlo A, Coffman KJ, Dantonio A, Di L, Eng H, Ferre R, Gajiwala KS, Gibson SA, Greasley SE, Hurst BL, Kadar EP, Kalgutkar AS, Lee JC, Lee J, Liu W, Mason SW, Noell S, Novak JJ, Obach RS, Ogilvie K, Patel NC, Pettersson M, Rai DK, Reese MR, Sammons MF, Sathish JG, Singh RSP, Steppan CM, Stewart AE, Tuttle JB, Updyke L, Verhoest PR, Wei L, Yang Q, Zhu Y. 2021. An oral SARS-CoV-2 M(pro) inhibitor clinical candidate for the treatment of COVID-19. Science 374:1586–1593. doi:.
Not in our library10.1126/science.abl4784
6.
Hammond J, Leister-Tebbe H, Gardner A, Abreu P, Bao W, Wisemandle W, Baniecki M, Hendrick VM, Damle B, Simón-Campos A, Pypstra R, Rusnak JM, EPIC-HR Investigators. 2022. Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19. N Engl J Med 386:1397–1408. doi:.
Not in our library10.1056/nejmoa2118542
7.
Wong CKH, Au ICH, Lau KTK, Lau EHY, Cowling BJ, Leung GM. 2022. Real-world 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 22:1681–1693. doi:.
Not in our library10.1016/s1473-3099(22)00507-2
8.
Reis S, Metzendorf M-I, Kuehn R, Popp M, Gagyor I, Kranke P, Meybohm P, Skoetz N, Weibel S. 2022. Nirmatrelvir combined with ritonavir for preventing and treating COVID-19. Cochrane Database Syst Rev 2022:Cd015395. doi:.
Not in our library10.1002/14651858.cd015395.pub2
9.
Efficacy and safety of three new oral antiviral treatment (molnupiravir, fluvoxamine and Paxlovid) for COVID-19：a meta-analysis · 2022
No notice
10.
Remdesivir, Molnupiravir and Nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern · 2022
No notice
11.
Abdelnabi R, Foo CS, Jochmans D, Vangeel L, De Jonghe S, Augustijns P, Mols R, Weynand B, Wattanakul T, Hoglund RM, Tarning J, Mowbray CE, Sjö P, Escudié F, Scandale I, Chatelain E, Neyts J. 2022. The oral protease inhibitor (PF-07321332) protects Syrian hamsters against infection with SARS-CoV-2 variants of concern. Nat Commun13:719. doi:.
Not in our library10.1038/s41467-022-28354-0
12.
Discovery of S-217622, a Noncovalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19 · 2022
No notice
13.
Mukae H, Yotsuyanagi H, Ohmagari N, Doi Y, Imamura T, Sonoyama T, Fukuhara T, Ichihashi G, Sanaki T, Baba K, Takeda Y, Tsuge Y, Uehara T. 2022. 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 66:e0069722. doi:.
Not in our library10.1128/aac.00697-22
14.
Arnold LL. 2022. Profile of PBI-0451 an orally administered 3CL protease inhibitor of SARS-CoV-2 for COVID-19. ICAR2022 meeting, Seattle, WA.
Not in our library
15.
Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19 · 2021
No notice
16.
Taylor N. 2022. Pfizer, in a rare COVID-19 setback, dumps Paxlovid's intravenous sibling in further blow to ACTIV-3. https://www.fiercebiotech.com/biotech/pfizer-a-rare-covid-19-setback-dumps-paxlovid-s-intravenous-sibling-to-leave-activ-3-future.
Not in our library
17.
Menéndez-Arias L, Delgado R. 2022. Update and latest advances in antiretroviral therapy. Trends Pharmacol Sci 43:16–29. doi:.
Not in our library10.1016/j.tips.2021.10.004
18.
Ison MG, Hayden FG, Hay AJ, Gubareva LV, Govorkova EA, Takashita E, McKimm-Breschkin JL. 2021. Influenza polymerase inhibitor resistance: Assessment of the current state of the art: a report of the isirv Antiviral group. Antiviral Res 194:105158. doi:.
Not in our library10.1016/j.antiviral.2021.105158
19.
Guo C, Wu Y, Zhang Y, Liu X, Li A, Gao M, Zhang T, Wu H, Chen G, Huang X. 2021. Transmitted drug resistance in antiretroviral therapy-naive persons with acute/early/primary HIV infection: a systematic review and meta-analysis. Front Pharmacol 12:718763. doi:.
Not in our library10.3389/fphar.2021.718763
20.
He W, Zhang W, Yan H, Xu H, Xie Y, Wu Q, Wang C, Dong G. 2021. Distribution and evolution of H1N1 influenza A viruses with adamantanes-resistant mutations worldwide from 1918 to 2019. J Med Virol 93:3473–3483. doi:.
Not in our library10.1002/jmv.26670
21.
Focosi D, Maggi F, McConnell S, Casadevall A. 2022. 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 198:105247. doi:.
Not in our library10.1016/j.antiviral.2022.105247
22.
Mutations in the SARS-CoV-2 RNA-dependent RNA polymerase confer resistance to remdesivir by distinct mechanisms · 2022
No notice
23.
Hogan JI, Duerr R, Dimartino D, Marier C, Hochman SE, Mehta S, Wang G, Heguy A. 2022. Remdesivir resistance in transplant recipients with persistent coronavirus disease 2019 (COVID-19). Clin Infect Dis ciac769. doi:.
Not in our library10.1093/cid/ciac769
24.
Hoffman RL, Kania RS, Brothers MA, Davies JF, Ferre RA, Gajiwala KS, He M, Hogan RJ, Kozminski K, Li LY, Lockner JW, Lou J, Marra MT, Mitchell LJ, Murray BW, Nieman JA, Noell S, Planken SP, Rowe T, Ryan K, Smith GJ, Solowiej JE, Steppan CM, Taggart B. 2020. Discovery of ketone-based covalent inhibitors of coronavirus 3CL proteases for the potential therapeutic treatment of COVID-19. J Med Chem 63:12725–12747. doi:.
Not in our library10.1021/acs.jmedchem.0c01063
25.
Thi Nhu Thao T, Labroussaa F, Ebert N, V'kovski P, Stalder H, Portmann J, Kelly J, Steiner S, Holwerda M, Kratzel A, Gultom M, Schmied K, Laloli L, Hüsser L, Wider M, Pfaender S, Hirt D, Cippà V, Crespo-Pomar S, Schröder S, Muth D, Niemeyer D, Corman VM, Müller MA, Drosten C, Dijkman R, Jores J, Thiel V. 2020. Rapid reconstruction of SARS-CoV-2 using a synthetic genomics platform. Nature 582:561–565. doi:.
Not in our library10.1038/s41586-020-2294-9
26.
Gain-of-Signal Assays for Probing Inhibition of SARS-CoV-2 Mpro/3CLpro in Living Cells · 2022
Not checked
27.
Gurard-Levin ZA, Liu C, Jekle A, Jaisinghani R, Ren S, Vandyck K, Jochmans D, Leyssen P, Neyts J, Blatt LM, Beigelman L, Symons JA, Raboisson P, Scholle MD, Deval J. 2020. Evaluation of SARS-CoV-2 3C-like protease inhibitors using self-assembled monolayer desorption ionization mass spectrometry. Antiviral Res 182:104924. doi:.
Not in our library10.1016/j.antiviral.2020.104924
28.
Ligand-induced Dimerization of Middle East Respiratory Syndrome (MERS) Coronavirus nsp5 Protease (3CLpro) · 2015
No notice
29.
Zephyr J, Yilmaz NK, Schiffer CA. 2021. Viral proteases: structure, mechanism and inhibition. Enzymes 50:301–333. doi:.
Not in our library10.1016/bs.enz.2021.09.004
30.
SARS-CoV-2 escape from a highly neutralizing COVID-19 convalescent plasma · 2021
No notice
31.
Lee JT, Yang Q, Gribenko A, Perrin BS, Zhu Y, Cardin R, Liberator PA, Anderson AS, Hao L. 2022. Genetic surveillance of SARS-CoV-2 M(pro) reveals high sequence and structural conservation prior to the introduction of protease inhibitor Paxlovid. mBio 13:e0086922. doi:.
Not in our library10.1128/mbio.00869-22
32.
Pfizer Laboratories. 2022. Fact sheet for healthcare providers: emergency use authorization for Paxlovid. https://labeling.pfizer.com/ShowLabeling.aspx?id=16474.
Not in our library
33.
Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir · 2022
No notice
34.
Nirmatrelvir-resistant SARS-CoV-2 variants with high fitness in an infectious cell culture system · 2022
No notice
35.
SARS-CoV-2 3CL pro mutations selected in a VSV-based system confer resistance to nirmatrelvir, ensitrelvir, and GC376 · 2023
No notice
36.
Flynn JM, Samant N, Schneider-Nachum G, Barkan DT, Yilmaz NK, Schiffer CA, Moquin SA, Dovala D, Bolon DN. 2022. Comprehensive fitness landscape of SARS-CoV-2 Mpro reveals insights into viral resistance mechanisms. Elife 11:e77433. doi:.
Not in our library10.7554/elife.77433
37.
STAT2 signaling restricts viral dissemination but drives severe pneumonia in SARS-CoV-2 infected hamsters · 2020
No notice
38.
Liu C, Boland S, Scholle MD, Bardiot D, Marchand A, Chaltin P, Blatt LM, Beigelman L, Symons JA, Raboisson P, Gurard-Levin ZA, Vandyck K, Deval J. 2021. Dual inhibition of SARS-CoV-2 and human rhinovirus with protease inhibitors in clinical development. Antiviral Res 187:105020. doi:.
Not in our library10.1016/j.antiviral.2021.105020
39.
Jochmans D, Leyssen P, Neyts J. 2012. A novel method for high-throughput screening to quantify antiviral activity against viruses that induce limited CPE. J Virol Methods 183:176–179. doi:.
Not in our library10.1016/j.jviromet.2012.04.011

Cited by papers we hold 2

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.

Are you an author?

Is this your paper?

Claim it to add your note and be paid when agents cite it. Free.