Bromodomain and extraterminal (BET) protein inhibitor, apabetalone, reduces ACE2 expression and attenuates SARS-CoV-2 infection in vitro

• Published in: European heart journal 2021-10, Vol.42 (Supplement_1)
• Main Authors: Gilham, D, Smith, A L, Fu, L, Moore, D Y, Muralidharan, A, Reid, S P M, Stotz, S C, Johansson, J O, Sweeney, M, Wong, N C W, El-Gamal, D, Kulikowski, E
• Format: Article
• Language: English
• Subjects: Abstract Supplement
• ISSN: 0195-668X; 1522-9645
• DOI: 10.1093/eurheartj/ehab724.3267

Abstract Background/Introduction SARS-CoV-2 causes life threatening COVID-19 complications including acute coronary syndrome, venous thromboembolism, hyperinflammation and damage in multiple tissues. The SARS-CoV-2 “spike protein” binds cell surface receptors including angiotensin-converting enzyme 2 (ACE2) for entry into host cells to initiate infection. Host cell dipeptidyl peptidase-4 (DPP4 / CD26) is implicated as a cofactor in uptake. Recent evidence indicates expression of factors involved in SARS-CoV-2 uptake into host cells is regulated by BET proteins, epigenetic readers modulating gene expression. Apabetalone, the most clinically advanced BET inhibitor (BETi), is in phase 3 trials for cardiovascular disease (CVD) (a,b). In cultured human cardiomyocytes, apabetalone suppressed infection with SARS-CoV-2 and prevented dysfunction of cardiac organoids induced by the cytokine-storm that arises in patients with severe symptoms (c). However, anti-viral properties of apabetalone in other cell types are not known. Purpose To examine effects of apabetalone on SARS-CoV-2 infection in cell culture via downregulated expression of cell surface receptors involved in viral entry. Cell systems used mimic initial sites of infection in the lung as well as cell types contributing to complications in late stages of infection. Methods Gene expression was measured by real-time PCR, protein levels by immunoblot or flow cytometry, and binding of recombinant SARS-CoV-2 spike protein by flow cytometry. Infection with SARS-CoV-2 was determined in a BSL3 facility. Infectivity was quantified by determining levels of viral spike protein amongst total cells via imaging on an Operetta CLS. Results In Calu-3, a human bronchial epithelial cell line, apabetalone dose-dependently downregulated ACE2 gene expression (up to 98%), reduced ACE2 protein levels (up to 84%) and diminished binding of SARS-CoV-2 spike protein (up to 77%, p