TY - JOUR T1 - Pharmacological inhibition of bromodomain and extra-terminal proteins induces NRF-2-mediated inhibition of SARS-CoV-2 replication and is subject to viral antagonism JF - bioRxiv DO - 10.1101/2022.09.22.508962 SP - 2022.09.22.508962 AU - Baxolele Mhlekude AU - Dylan Postmus AU - January Weiner, 3rd AU - Saskia Stenzel AU - Francisco J. Zapatero-Belinchón AU - Ruth Olmer AU - Jenny Jansen AU - Anja Richter AU - Julian Heinze AU - Nicolas Heinemann AU - Barbara Mühlemann AU - Simon Schroeder AU - Terry C. Jones AU - Marcel Alexander Müller AU - Christian Drosten AU - Andreas Pich AU - Volker Thiel AU - Ulrich Martin AU - Daniela Niemeyer AU - Gisa Gerold AU - Dieter Beule AU - Christine Goffinet Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/09/23/2022.09.22.508962.abstract N2 - Inhibitors of bromodomain and extra-terminal proteins (iBETs), including JQ-1, have been suggested as potential therapeutics against SARS-CoV-2 infection. However, molecular mechanisms underlying JQ-1-induced antiviral activity and its susceptibility to viral antagonism remain incompletely understood. iBET treatment transiently inhibited infection by SARS-CoV-2 variants and SARS-CoV, but not MERS-CoV. Our functional assays confirmed JQ-1-mediated downregulation of ACE2 expression and multi-omics analysis uncovered induction of an antiviral NRF-2-mediated cytoprotective response as an additional antiviral component of JQ-1 treatment. Serial passaging of SARS-CoV-2 in the presence of JQ-1 resulted in predominance of ORF6-deficient variants. JQ-1 antiviral activity was transient in human bronchial airway epithelial cells (hBAECs) treated prior to infection and absent when administered therapeutically. We propose that JQ-1 exerts pleiotropic effects that collectively induce a transient antiviral state that is ultimately nullified by an established SARS-CoV-2 infection, raising questions on their clinical suitability in the context of COVID-19.Competing Interest StatementThe authors have declared no competing interest. ER -