BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection PMID: 33811809

ADC Targets in Oncology

2026-04-10

BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection

Cell. 2021 Apr 15;184(8):2167-2182.e22. doi: 10.1016/j.cell.2021.03.026.

Richard J Mills ¹ , Sean J Humphrey ² , Patrick R J Fortuna ¹ , Mary Lor ¹ , Simon R Foster ¹ , Gregory A Quaife-Ryan ¹ , Rebecca L Johnston ¹ , Troy Dumenil ¹ , Cameron Bishop ¹ , Rajeev Rudraraju ³ , Daniel J Rawle ¹ , Thuy Le ¹ , Wei Zhao ⁴ , Leo Lee ⁴ , Charley Mackenzie-Kludas ⁴ , Neda R Mehdiabadi ⁵ , Christopher Halliday ⁶ , Dean Gilham ⁶ , Li Fu ⁶ , Stephen J Nicholls ⁷ , Jan Johansson ⁸ , Michael Sweeney ⁸ , Norman C W Wong ⁶ , Ewelina Kulikowski ⁶ , Kamil A Sokolowski ⁹ , Brian W C Tse ⁹ , Lynn Devilée ¹ , Holly K Voges ¹ , Liam T Reynolds ¹ , Sophie Krumeich ¹ , Ellen Mathieson ¹ , Dad Abu-Bonsrah ¹⁰ , Kathy Karavendzas ⁵ , Brendan Griffen ¹¹ , Drew Titmarsh ¹¹ , David A Elliott ⁵ , James McMahon ¹² , Andreas Suhrbier ¹³ , Kanta Subbarao ¹⁴ , Enzo R Porrello ¹⁵ , Mark J Smyth ¹ , Christian R Engwerda ¹ , Kelli P A MacDonald ¹ , Tobias Bald ¹⁶ , David E James ¹⁷ , James E Hudson ¹⁸

Affiliations

1. QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia.
2. Charles Perkins Centre, School of Life and Environmental Science, The University of Sydney, Sydney 2006, NSW, Australia.
3. The WHO Collaborating Centre for Reference and Research on Influenza, The Peter Doherty Institute for Infection and Immunity, Melbourne 3000, VIC, Australia; Department of Microbiology and Immunology, The University of Melbourne, Melbourne 3052, VIC, Australia; The Peter Doherty Institute for Infection and Immunity, Melbourne 3000, VIC, Australia.
4. The Peter Doherty Institute for Infection and Immunity, Melbourne 3000, VIC, Australia.
5. Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne 3052, VIC, Australia.
6. Resverlogix Corp., Calgary T3E 6L1, AB, Canada.
7. Victorian Heart Hospital, Monash University, Clayton 3168, VIC, Australia.
8. Resverlogix Corp., San Francisco, CA 94104, USA.
9. Preclinical Imaging Facility, Translational Research Institute, Brisbane, QLD, Australia.
10. Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne 3052, VIC, Australia; Department of Paediatrics, The University of Melbourne, Melbourne 3052, VIC, Australia.
11. Dynomics Inc., San Mateo, CA 94401, USA; Dynomics Pty Ltd, Brisbane 4000, QLD, Australia.
12. Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne 3004, VIC, Australia; Department of Infectious Diseases, Monash Medical Centre, Clayton 3168, VIC, Australia.
13. QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia; GVN Center of Excellence, Australian Infectious Diseases Research Centre, Brisbane, QLD, Australia.
14. The WHO Collaborating Centre for Reference and Research on Influenza, The Peter Doherty Institute for Infection and Immunity, Melbourne 3000, VIC, Australia; The Peter Doherty Institute for Infection and Immunity, Melbourne 3000, VIC, Australia.
15. Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne 3052, VIC, Australia; Department of Physiology, School of Biomedical Sciences, The University of Melbourne, Melbourne 3052, VIC, Australia.
16. QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia; Institute of Experimental Oncology, University Hospital Bonn, Bonn 53127, Germany.
17. Charles Perkins Centre, School of Life and Environmental Science, The University of Sydney, Sydney 2006, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney 2006, NSW, Australia.
18. QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia. Electronic address: [email protected].

Abstract

Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined but could be through direct cardiac Infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA Sequencing. We identify an inflammatory "cytokine-storm", a cocktail of interferon gamma, interleukin 1β, and poly(I:C), induced diastolic dysfunction. Bromodomain-containing protein 4 is activated along with a viral response that is consistent in both human cardiac organoids (hCOs) and hearts of SARS-CoV-2-infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCOs and completely prevent cardiac dysfunction and death in a mouse cytokine-storm model. Additionally, BETi decreases transcription of genes in the viral response, decreases ACE2 expression, and reduces SARS-CoV-2 Infection of cardiomyocytes. Together, BETi, including the Food and Drug Administration (FDA) breakthrough designated drug, apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage.

Keywords

Bromodomain and extraterminal family inhibitors; COVID-19; drug discovery; heart; inflammation; organoids.