Pharmacological inhibition of bromodomain and extra-terminal proteins induces an NRF-2-mediated antiviral state that is subverted by SARS-CoV-2 infection

• Published in: PLoS pathogens Vol. 19; no. 9; p. e1011657
• Main Authors: Mhlekude, Baxolele, Postmus, Dylan, Stenzel, Saskia, Weiner, 3rd, January, Jansen, Jenny, Zapatero-Belinchón, Francisco J, Olmer, Ruth, Richter, Anja, Heinze, Julian, Heinemann, Nicolas, Mühlemann, Barbara, Schroeder, Simon, Jones, Terry C, Müller, Marcel A, Drosten, Christian, Pich, Andreas, Thiel, Volker, Martin, Ulrich, Niemeyer, Daniela, Gerold, Gisa, Beule, Dieter, Goffinet, Christine
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 25.09.2023; Public Library of Science (PLoS)
• Subjects: ACE2; Analysis; Angiotensin; Angiotensin-converting enzyme 2; Antiviral activity; Antiviral Agents - pharmacology; Antiviral state; Biological response modifiers; Biology and life sciences; Cell culture; Chromatin; Consent; COVID-19; Enzymes; Epigenetics; Epithelial cells; Epithelium; Ethics; GA-binding protein; Genes; Genomes; Health aspects; Humans; Infections; Interferon; Interferon Type I - pharmacology; Lung transplants; Medicine and health sciences; Middle East respiratory syndrome; Molecular modelling; Patients; Penicillin; Peptidyl-dipeptidase A; Pharmacology; Proteins; Proteomes; Replication; RNA; RNA viruses; SARS-CoV-2 - metabolism; Scientific equipment and supplies industry; Severe acute respiratory syndrome coronavirus 2; Transcriptomes; Viral diseases; Viral Proteins - metabolism; Viruses; Canada; United States; Germany
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1011657

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.