Nirmatrelvir-Resistant Mutations in SARS-CoV-2 Mpro Enhance Host Immune Evasion via Cleavage of NF-κB Essential Modulator
Merrilee Thomas, Thom Hughes
doi:10.1101/2024.10.18.619137
Nirmatrelvir is a SARS-CoV-2 M pro inhibitor in Paxlovid. Patients treated with it often produce mutant viruses in which the M pro resists Nirmatrelvir inhibition. A common interpretation is that the mutations allow the virus to escape inhibition, but here we report that these mutations enable the protease to more effectively cleave the host protein NF-kappa-B essential modulator (NEMO), which weakens the immune response, improves viral replication, and may contribute to long COVID.
References
Authorization, Fact sheet for healthcare providers: Emergency use authorization for paxlovidtm
Barretto, The papain-like protease of severe acute respiratory syndrome coronavirus has deubiquitinating activity, J. Virol
Chathuranga, Negative regulation of NEMO signaling by the ubiquitin E3 ligase MARCH2, EMBO J
Duan, Molecular mechanisms of SARS-CoV-2 resistance to nirmatrelvir, Nature
Fu, Both Boceprevir and GC376 efficaciously inhibit SARS-CoV-2 by targeting its main protease, Nat. Commun
Hameedi, Structural and functional characterization of NEMO cleavage by SARS-CoV-2 3CLpro, Nat. Commun
Hu, Naturally Occurring Mutations of SARS-CoV-2 Main Protease Confer Drug Resistance to Nirmatrelvir, ACS Cent Sci
Huang, A new generation Mpro inhibitor with potent activity against SARS-CoV-2 Omicron variants, Signal Transduct Target Ther
Iketani, Functional map of SARS-CoV-2 3CL protease reveals tolerant and immutable sites, Cell Host Microbe
Iketani, Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir, Nature
Jochmans, 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
Luckow, Lee, Barry, Olins, Efficient generation of infectious recombinant baculoviruses by site-specific transposon-mediated insertion of foreign genes into a baculovirus genome propagated in Escherichia coli, J. Virol
Lytras, Xia, Hughes, Jiang, Robertson, The animal origin of SARS-CoV-2, Science
Markov, The evolution of SARS-CoV-2, Nat. Rev. Microbiol
Pérez-Vargas, 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
Shu, Mccauley, Gisaid, Global initiative on sharing all influenza datafrom vision to reality, Euro Surveill
Tan, Joyce, Tan, Hu, Wang, SARS-CoV-2 Main Protease Drug Design, Assay Development, and Drug Resistance Studies, Acc. Chem. Res
Tong, Evaluation of in vitro antiviral activity of SARS-CoV-2 Mpro inhibitor pomotrelvir and cross-resistance to nirmatrelvir resistance substitutions, Antimicrob. Agents Chemother
Ullrich, Ekanayake, Otting, Nitsche, Main protease mutants of SARS-CoV-2 variants remain susceptible to nirmatrelvir, Bioorg. Med. Chem. Lett
Wenzel, The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells, Nat. Neurosci
Xie, The SARS-unique domain (SUD) of SARS-CoV-2 nsp3 protein inhibits the antiviral immune responses through the NF-κB pathway, J. Med. Virol
Zhao, Structural basis for replicase polyprotein cleavage and substrate specificity of main protease from SARS-CoV-2, Proc. Natl. Acad. Sci. U. S. A
Zhou, Nirmatrelvir-resistant SARS-CoV-2 variants with high fitness in an infectious cell culture system, Sci Adv
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'abstract': '<jats:p>Nirmatrelvir is a SARS-CoV-2 Mpro inhibitor in Paxlovid. Patients treated with it '
'often produce mutant viruses in which the Mpro resists Nirmatrelvir inhibition. A common '
'interpretation is that the mutations allow the virus to escape inhibition, but here we report '
'that these mutations enable the protease to more effectively cleave the host protein '
'NF-kappa-B essential modulator (NEMO), which weakens the immune response, improves viral '
'replication, and may contribute to long COVID.</jats:p>',
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