Bromodomain and extraterminal protein inhibitor, apabetalone (Rvx-208), reduces ace2 expression and attenuates sars-cov-2 infection in vitro

Dean Gilham; Audrey L. Smith; Li Fu; Dalia Y. Moore; Abenaya Muralidharan; St Patrick M. Reid; Stephanie C. Stotz; Jan O. Johansson; Michael Sweeney; Norman C.W. Wong; Ewelina Kulikowski; Dalia El-Gamal

doi:10.3390/biomedicines9040437

Bromodomain and extraterminal protein inhibitor, apabetalone (Rvx-208), reduces ace2 expression and attenuates sars-cov-2 infection in vitro

Dean Gilham, Audrey L. Smith, Li Fu, Dalia Y. Moore, Abenaya Muralidharan, St Patrick M. Reid, Stephanie C. Stotz, Jan O. Johansson, Michael Sweeney, Norman C.W. Wong, Ewelina Kulikowski, Dalia El-Gamal

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

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 those of antiviral agents. Taken together, our study supports further evaluation of apabetalone to treat COVID-19, either alone or in combination with emerging therapeutics.

Original language	English (US)
Article number	437
Journal	Biomedicines
Volume	9
Issue number	4
DOIs	https://doi.org/10.3390/biomedicines9040437
State	Published - Apr 2021

Keywords

Angiotensin-converting enzyme 2 (ACE2)
Apabetalone
BET proteins
COVID-19
SARS-CoV-2

ASJC Scopus subject areas

Medicine (miscellaneous)
Biochemistry, Genetics and Molecular Biology(all)

Access to Document

10.3390/biomedicines9040437

Cite this

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., Kulikowski, E., & El-Gamal, D. (2021). Bromodomain and extraterminal protein inhibitor, apabetalone (Rvx-208), reduces ace2 expression and attenuates sars-cov-2 infection in vitro. Biomedicines, 9(4), Article 437. https://doi.org/10.3390/biomedicines9040437

Gilham, D, Smith, AL, Fu, L, Moore, DY, Muralidharan, A, Reid, SPM, Stotz, SC, Johansson, JO, Sweeney, M, Wong, NCW, Kulikowski, E & El-Gamal, D 2021, 'Bromodomain and extraterminal protein inhibitor, apabetalone (Rvx-208), reduces ace2 expression and attenuates sars-cov-2 infection in vitro', Biomedicines, vol. 9, no. 4, 437. https://doi.org/10.3390/biomedicines9040437

@article{08a7a8e4b3464d6aaf167acfd4093728,

title = "Bromodomain and extraterminal protein inhibitor, apabetalone (Rvx-208), reduces ace2 expression and attenuates sars-cov-2 infection in vitro",

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 those of antiviral agents. Taken together, our study supports further evaluation of apabetalone to treat COVID-19, either alone or in combination with emerging therapeutics.",

keywords = "Angiotensin-converting enzyme 2 (ACE2), Apabetalone, BET proteins, COVID-19, SARS-CoV-2",

author = "Dean Gilham and Smith, {Audrey L.} and Li Fu and Moore, {Dalia Y.} and Abenaya Muralidharan and Reid, {St Patrick M.} and Stotz, {Stephanie C.} and Johansson, {Jan O.} and Michael Sweeney and Wong, {Norman C.W.} and Ewelina Kulikowski and Dalia El-Gamal",

note = "Funding Information: Authors on this manuscript are supported in part by a COVID-19 Rapid Response Grant from the College of Medicine at UNMC (to D.E.-G. and S.P.M.R.) and by UNMC start-up funds (to D.E.-G.). Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2021",

month = apr,

doi = "10.3390/biomedicines9040437",

language = "English (US)",

volume = "9",

journal = "Biomedicines",

issn = "2227-9059",

publisher = "MDPI AG",

number = "4",

}

TY - JOUR

T1 - Bromodomain and extraterminal protein inhibitor, apabetalone (Rvx-208), reduces ace2 expression and attenuates sars-cov-2 infection in vitro

AU - Gilham, Dean

AU - Smith, Audrey L.

AU - Fu, Li

AU - Moore, Dalia Y.

AU - Muralidharan, Abenaya

AU - Reid, St Patrick M.

AU - Stotz, Stephanie C.

AU - Johansson, Jan O.

AU - Sweeney, Michael

AU - Wong, Norman C.W.

AU - Kulikowski, Ewelina

AU - El-Gamal, Dalia

N1 - Funding Information: Authors on this manuscript are supported in part by a COVID-19 Rapid Response Grant from the College of Medicine at UNMC (to D.E.-G. and S.P.M.R.) and by UNMC start-up funds (to D.E.-G.). Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2021/4

Y1 - 2021/4

N2 - 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 those of antiviral agents. Taken together, our study supports further evaluation of apabetalone to treat COVID-19, either alone or in combination with emerging therapeutics.

AB - 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 those of antiviral agents. Taken together, our study supports further evaluation of apabetalone to treat COVID-19, either alone or in combination with emerging therapeutics.

KW - Angiotensin-converting enzyme 2 (ACE2)

KW - Apabetalone

KW - BET proteins

KW - COVID-19

KW - SARS-CoV-2

UR - http://www.scopus.com/inward/record.url?scp=85104935357&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85104935357&partnerID=8YFLogxK

U2 - 10.3390/biomedicines9040437

DO - 10.3390/biomedicines9040437

M3 - Article

C2 - 33919584

AN - SCOPUS:85104935357

SN - 2227-9059

VL - 9

JO - Biomedicines

JF - Biomedicines

IS - 4

M1 - 437

ER -

Bromodomain and extraterminal protein inhibitor, apabetalone (Rvx-208), reduces ace2 expression and attenuates sars-cov-2 infection in vitro

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this