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bioRxiv · 10.1101/2021.03.10.432949

Bromodomain and Extraterminal Protein Inhibitor, Apabetalone (RVX-208), Reduces ACE2 Expression and Attenuates SARS-CoV-2 Infection in vitro

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.·Kulikowski, E.·El-Gamal, D.
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Abstract

Effective therapeutics are urgently needed to counter infection and improve outcomes for patients suffering from COVID-19 and to combat this pandemic. Manipulation of epigenetic machinery to influence viral infectivity of host cells is a relatively unexplored area. The bromodomain and extraterminal (BET) family of epigenetic readers have been reported to modulate SARS-CoV-2 infection. Herein, we demonstrate apabetalone, the most clinical advanced BET inhibitor, downregulates expression of cell surface receptors involved in SARS-CoV-2 entry, including angiotensin-converting enzyme 2 (ACE2) and dipeptidyl-peptidase 4 (DPP4 or CD26) in SARS-CoV-2 permissive cells. Moreover, we show that apabetalone inhibits SARS-CoV-2 infection in vitro to levels comparable to antiviral agents. Taken together, our study supports further evaluation of apabetalone to treat COVID-19, either alone or in combination with emerging therapeutics. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=192 SRC="FIGDIR/small/432949v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@127e6c4org.highwire.dtl.DTLVardef@9f6d3aorg.highwire.dtl.DTLVardef@bbfe3borg.highwire.dtl.DTLVardef@2ffad8_HPS_FORMAT_FIGEXP M_FIG C_FIG

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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., Kulikowski, E., El-Gamal, D.. 2021-03-11. Bromodomain and Extraterminal Protein Inhibitor, Apabetalone (RVX-208), Reduces ACE2 Expression and Attenuates SARS-CoV-2 Infection in vitro. https://doi.org/10.1101/2021.03.10.432949

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