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Pharmacological inhibition of bromodomain and extra-terminal proteins induces NRF-2-mediated inhibition of SARS-CoV-2 replication and is subject to viral antagonism

View ORCID ProfileBaxolele Mhlekude, Dylan Postmus, January Weiner 3rd, Saskia Stenzel, Francisco J. Zapatero-Belinchón, Ruth Olmer, Jenny Jansen, Anja Richter, Julian Heinze, Nicolas Heinemann, View ORCID ProfileBarbara Mühlemann, Simon Schroeder, View ORCID ProfileTerry C. Jones, View ORCID ProfileMarcel Alexander Müller, Christian Drosten, Andreas Pich, Volker Thiel, Ulrich Martin, View ORCID ProfileDaniela Niemeyer, Gisa Gerold, Dieter Beule, View ORCID ProfileChristine Goffinet
doi: https://doi.org/10.1101/2022.09.22.508962
Baxolele Mhlekude
1Institute of Virology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
2Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany
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  • ORCID record for Baxolele Mhlekude
Dylan Postmus
1Institute of Virology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
2Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany
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January Weiner 3rd
2Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany
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Saskia Stenzel
1Institute of Virology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
2Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany
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Francisco J. Zapatero-Belinchón
3Department of Biochemistry, University of Veterinary Medicine Hannover, 30559 Hannover, Germany
4Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, 30625 Hannover, Germany
5Department of Clinical Microbiology, Virology & Wallenberg Centre for Molecular Medicine (WCMM), Umeå University, SE-90185 Umeå, Sweden
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Ruth Olmer
6Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery, REBIRTH - Center for Translational Regenerative Medicine, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover Medical School, 30625 Hannover, Germany
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Jenny Jansen
1Institute of Virology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
2Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany
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Anja Richter
1Institute of Virology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
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Julian Heinze
1Institute of Virology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
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Nicolas Heinemann
1Institute of Virology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
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Barbara Mühlemann
1Institute of Virology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
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Simon Schroeder
1Institute of Virology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
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Terry C. Jones
1Institute of Virology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
7Centre for Pathogen Evolution, Department of Zoology, University of Cambridge, Downing St., Cambridge, CB2 3EJ, U.K
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Marcel Alexander Müller
1Institute of Virology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
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Christian Drosten
1Institute of Virology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
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Andreas Pich
8Institute of Toxicology, Hannover Medical School, Core Facility Proteomics, 30629 Hannover, Germany
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Volker Thiel
9Institute of Virology and Immunology (IVI), University of Bern, 3001 Bern, Switzerland
10Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, 30 3001 Bern, Switzerland
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Ulrich Martin
6Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery, REBIRTH - Center for Translational Regenerative Medicine, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover Medical School, 30625 Hannover, Germany
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Daniela Niemeyer
1Institute of Virology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
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Gisa Gerold
3Department of Biochemistry, University of Veterinary Medicine Hannover, 30559 Hannover, Germany
4Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, 30625 Hannover, Germany
5Department of Clinical Microbiology, Virology & Wallenberg Centre for Molecular Medicine (WCMM), Umeå University, SE-90185 Umeå, Sweden
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Dieter Beule
2Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany
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Christine Goffinet
1Institute of Virology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
2Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany
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  • For correspondence: christine.goffinet@charite.de
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ABSTRACT

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 Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted September 23, 2022.
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Pharmacological inhibition of bromodomain and extra-terminal proteins induces NRF-2-mediated inhibition of SARS-CoV-2 replication and is subject to viral antagonism
Baxolele Mhlekude, Dylan Postmus, January Weiner 3rd, Saskia Stenzel, Francisco J. Zapatero-Belinchón, Ruth Olmer, Jenny Jansen, Anja Richter, Julian Heinze, Nicolas Heinemann, Barbara Mühlemann, Simon Schroeder, Terry C. Jones, Marcel Alexander Müller, Christian Drosten, Andreas Pich, Volker Thiel, Ulrich Martin, Daniela Niemeyer, Gisa Gerold, Dieter Beule, Christine Goffinet
bioRxiv 2022.09.22.508962; doi: https://doi.org/10.1101/2022.09.22.508962
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Pharmacological inhibition of bromodomain and extra-terminal proteins induces NRF-2-mediated inhibition of SARS-CoV-2 replication and is subject to viral antagonism
Baxolele Mhlekude, Dylan Postmus, January Weiner 3rd, Saskia Stenzel, Francisco J. Zapatero-Belinchón, Ruth Olmer, Jenny Jansen, Anja Richter, Julian Heinze, Nicolas Heinemann, Barbara Mühlemann, Simon Schroeder, Terry C. Jones, Marcel Alexander Müller, Christian Drosten, Andreas Pich, Volker Thiel, Ulrich Martin, Daniela Niemeyer, Gisa Gerold, Dieter Beule, Christine Goffinet
bioRxiv 2022.09.22.508962; doi: https://doi.org/10.1101/2022.09.22.508962

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