%0 Journal Article %1 10.1371/journal.ppat.1011657 %A Mhlekude, B %A Postmus, D %A Stenzel, S %A Weiner, J, 3rd %A Jansen, J %A Zapatero-Belinchon, F J %A Olmer, R %A Richter, A %A Heinze, J %A Heinemann, N %A Muhlemann, B %A Schroeder, S %A Jones, T C %A Muller, M A %A Drosten, C %A Pich, A %A Thiel, V %A Martin, U %A Niemeyer, D %A Gerold, G %A Beule, D %A Goffinet, C %D 2023 %I Public Library of Science %J PLoS Pathog %K pietschmann %N 9 %P e1011657 %R 10.1371/journal.ppat.1011657 %T Pharmacological inhibition of bromodomain and extra-terminal proteins induces an NRF-2-mediated antiviral state that is subverted by SARS-CoV-2 infection %U https://pubmed.ncbi.nlm.nih.gov/37747932/ %V 19 %X Inhibitors of bromodomain and extra-terminal proteins (iBETs), including JQ-1, have been suggested as potential prophylactics against SARS-CoV-2 infection. However, molecular mechanisms underlying JQ-1-mediated antiviral activity and its susceptibility to viral subversion remain incompletely understood. Pretreatment of cells with iBETs inhibited infection by SARS-CoV-2 variants and SARS-CoV, but not MERS-CoV. The antiviral activity manifested itself by reduced reporter expression of recombinant viruses, and reduced viral RNA quantities and infectious titers in the culture supernatant. While we confirmed JQ-1-mediated downregulation of expression of angiotensin-converting enzyme 2 (ACE2) and interferon-stimulated genes (ISGs), multi-omics analysis addressing the chromatin accessibility, transcriptome and proteome uncovered induction of an antiviral nuclear factor erythroid 2-related factor 2 (NRF-2)-mediated cytoprotective response as an additional mechanism through which JQ-1 inhibits SARS-CoV-2 replication. Pharmacological inhibition of NRF-2, and knockdown of NRF-2 and its target genes reduced JQ-1-mediated inhibition of SARS-CoV-2 replication. Serial passaging of SARS-CoV-2 in the presence of JQ-1 resulted in predominance of ORF6-deficient variant, which exhibited resistance to JQ-1 and increased sensitivity to exogenously administered type I interferon (IFN-I), suggesting a minimised need for SARS-CoV-2 ORF6-mediated repression of IFN signalling in the presence of JQ-1. Importantly, JQ-1 exhibited a transient antiviral activity when administered prophylactically in human airway bronchial epithelial cells (hBAECs), which was gradually subverted by SARS-CoV-2, and no antiviral activity when administered therapeutically following an established infection. We propose that JQ-1 exerts pleiotropic effects that collectively induce an antiviral state in the host, which is ultimately nullified by SARS-CoV-2 infection, raising questions about the clinical suitability of the iBETs in the context of COVID-19.

@article{10.1371/journal.ppat.1011657, abstract = {Inhibitors of bromodomain and extra-terminal proteins (iBETs), including JQ-1, have been suggested as potential prophylactics against SARS-CoV-2 infection. However, molecular mechanisms underlying JQ-1-mediated antiviral activity and its susceptibility to viral subversion remain incompletely understood. Pretreatment of cells with iBETs inhibited infection by SARS-CoV-2 variants and SARS-CoV, but not MERS-CoV. The antiviral activity manifested itself by reduced reporter expression of recombinant viruses, and reduced viral RNA quantities and infectious titers in the culture supernatant. While we confirmed JQ-1-mediated downregulation of expression of angiotensin-converting enzyme 2 (ACE2) and interferon-stimulated genes (ISGs), multi-omics analysis addressing the chromatin accessibility, transcriptome and proteome uncovered induction of an antiviral nuclear factor erythroid 2-related factor 2 (NRF-2)-mediated cytoprotective response as an additional mechanism through which JQ-1 inhibits SARS-CoV-2 replication. Pharmacological inhibition of NRF-2, and knockdown of NRF-2 and its target genes reduced JQ-1-mediated inhibition of SARS-CoV-2 replication. Serial passaging of SARS-CoV-2 in the presence of JQ-1 resulted in predominance of ORF6-deficient variant, which exhibited resistance to JQ-1 and increased sensitivity to exogenously administered type I interferon (IFN-I), suggesting a minimised need for SARS-CoV-2 ORF6-mediated repression of IFN signalling in the presence of JQ-1. Importantly, JQ-1 exhibited a transient antiviral activity when administered prophylactically in human airway bronchial epithelial cells (hBAECs), which was gradually subverted by SARS-CoV-2, and no antiviral activity when administered therapeutically following an established infection. We propose that JQ-1 exerts pleiotropic effects that collectively induce an antiviral state in the host, which is ultimately nullified by SARS-CoV-2 infection, raising questions about the clinical suitability of the iBETs in the context of COVID-19.}, added-at = {2023-10-19T11:38:15.000+0200}, author = {Mhlekude, B and Postmus, D and Stenzel, S and {Weiner, J}, 3rd and Jansen, J and Zapatero-Belinchon, F J and Olmer, R and Richter, A and Heinze, J and Heinemann, N and Muhlemann, B and Schroeder, S and Jones, T C and Muller, M A and Drosten, C and Pich, A and Thiel, V and Martin, U and Niemeyer, D and Gerold, G and Beule, D and Goffinet, C}, biburl = {https://www.bibsonomy.org/bibtex/243f0247e007dac3a8b191d75be89f195/pietschmann}, doi = {10.1371/journal.ppat.1011657}, interhash = {d9ad595a03e3aa12514014cf6b4471ac}, intrahash = {43f0247e007dac3a8b191d75be89f195}, journal = {PLoS Pathog}, keywords = {pietschmann}, month = {09}, number = 9, pages = {e1011657}, publisher = {Public Library of Science}, timestamp = {2024-01-04T16:47:17.000+0100}, title = {Pharmacological inhibition of bromodomain and extra-terminal proteins induces an NRF-2-mediated antiviral state that is subverted by SARS-CoV-2 infection}, url = {https://pubmed.ncbi.nlm.nih.gov/37747932/}, volume = 19, year = 2023 }