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.
Competing Interest Statement
DG, LF, SCS, JOJ, MS, NCWW, and EK are employed by Resverlogix and may hold stock and/or stock options. ALS, DYM, AM, SPMR, and DE have no conflicts of interest, financial or otherwise.
Footnotes
Author e-mail addresses: Dean Gilham dean{at}resverlogix.com, Audrey L Smith audrey.smith{at}unmc.edu, Li Fu li{at}resverlogix.com, Dalia Y Moore dalia.moore{at}unmc.edu, Abenaya Muralidharan abenaya.muralidharan{at}unmc.edu, St. Patrick M Reid patrick.reid{at}unmc.edu, Stephanie C Stotz sstotz{at}resverlogix.com, Jan O Johansson jan{at}resverlogix.com, Michael Sweeney msweeney{at}resverlogix.com, Norman CW Wong norm{at}resverlogix.com, Ewelina Kulikowski ewelina{at}resverlogix.com, and Dalia El-Gamal dalia.elgamal{at}unmc.edu
Abbreviations
- ACE2
- angiotensin-converting enzyme 2
- ARDS
- acute respiratory distress syndrome
- BET
- bromodomain and extraterminal
- BETi
- bromodomain and extraterminal protein inhibitor
- BD
- bromodomain
- COVID-19
- novel coronavirus disease of 2019
- DPP4
- dipeptidyl-peptidase 4
- DMSO
- dimethyl sulfoxide
- IL
- interleukin
- MTS
- 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium
- PHH
- primary human hepatocytes
- PROTAC
- proteolysis targeting chimera
- TMPRSS2
- transmembrane serine protease 2
- TNF-α
- tumor necrosis factor-alpha
