BET bromodomain inhibitors show anti-papillomavirus activity in vitro and block CRPV wart growth in vivo

Mary A. Morse, Karla K. Balogh, Sarah A. Brendle, Colin A. Campbell, Mao X. Chen, Rebecca C. Furze, Isobel L. Harada, Ian D. Holyer, Umesh Kumar, Kevin Lee, Rab K. Prinjha, Martin Rüdiger, Jonathan T. Seal, Simon Taylor, Jason Witherington, Neil D. Christensen

Research output: Contribution to journalArticle

Abstract

The DNA papillomaviruses infect squamous epithelium and can cause persistent, benign and sometimes malignant hyperproliferative lesions. Effective antiviral drugs to treat human papillomavirus (HPV) infection are lacking and here we investigate the anti-papillomavirus activity of novel epigenetic targeting drugs, BET bromodomain inhibitors. Bromodomain and Extra-Terminal domain (BET) proteins are host proteins which regulate gene transcription, they bind acetylated lysine residues in histones and non-histone proteins via bromodomains, functioning as scaffold proteins in the formation of transcriptional complexes at gene regulatory regions. The BET protein BRD4 has been shown to be involved in the papillomavirus life cycle, as a co-factor for viral E2 and also mediating viral partitioning in some virus types. We set out to study the activity of small molecule BET bromodomain inhibitors in models of papillomavirus infection. Several BET inhibitors reduced HPV11 E1ˆE4 mRNA expression in vitro and topical therapeutic administration of an exemplar compound I-BET762, abrogated CRPV cutaneous wart growth in rabbits, demonstrating translation of anti-viral effects to efficacy in vivo. Additionally I-BET762 markedly reduced viability of HPV16 infected W12 cells compared to non-infected C33A cells. The molecular mechanism for the cytotoxicity to W12 cells is unknown but may be through blocking viral-dependent cell-survival factors. We conclude that these effects, across multiple papillomavirus types and in vivo, highlight the potential to target BET bromodomains to treat HPV infection.

Original languageEnglish (US)
Pages (from-to)158-165
Number of pages8
JournalAntiviral Research
Volume154
DOIs
StatePublished - Jun 2018

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Warts
Papillomavirus Infections
Growth
Topical Administration
Proteins
Nucleic Acid Regulatory Sequences
Drug Delivery Systems
Life Cycle Stages
Epigenomics
Histones
Genes
Lysine
Antiviral Agents
Cell Survival
Epithelium
Rabbits
Viruses
Messenger RNA
Skin
DNA

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Virology

Cite this

Morse, Mary A. ; Balogh, Karla K. ; Brendle, Sarah A. ; Campbell, Colin A. ; Chen, Mao X. ; Furze, Rebecca C. ; Harada, Isobel L. ; Holyer, Ian D. ; Kumar, Umesh ; Lee, Kevin ; Prinjha, Rab K. ; Rüdiger, Martin ; Seal, Jonathan T. ; Taylor, Simon ; Witherington, Jason ; Christensen, Neil D. / BET bromodomain inhibitors show anti-papillomavirus activity in vitro and block CRPV wart growth in vivo. In: Antiviral Research. 2018 ; Vol. 154. pp. 158-165.
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abstract = "The DNA papillomaviruses infect squamous epithelium and can cause persistent, benign and sometimes malignant hyperproliferative lesions. Effective antiviral drugs to treat human papillomavirus (HPV) infection are lacking and here we investigate the anti-papillomavirus activity of novel epigenetic targeting drugs, BET bromodomain inhibitors. Bromodomain and Extra-Terminal domain (BET) proteins are host proteins which regulate gene transcription, they bind acetylated lysine residues in histones and non-histone proteins via bromodomains, functioning as scaffold proteins in the formation of transcriptional complexes at gene regulatory regions. The BET protein BRD4 has been shown to be involved in the papillomavirus life cycle, as a co-factor for viral E2 and also mediating viral partitioning in some virus types. We set out to study the activity of small molecule BET bromodomain inhibitors in models of papillomavirus infection. Several BET inhibitors reduced HPV11 E1ˆE4 mRNA expression in vitro and topical therapeutic administration of an exemplar compound I-BET762, abrogated CRPV cutaneous wart growth in rabbits, demonstrating translation of anti-viral effects to efficacy in vivo. Additionally I-BET762 markedly reduced viability of HPV16 infected W12 cells compared to non-infected C33A cells. The molecular mechanism for the cytotoxicity to W12 cells is unknown but may be through blocking viral-dependent cell-survival factors. We conclude that these effects, across multiple papillomavirus types and in vivo, highlight the potential to target BET bromodomains to treat HPV infection.",
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Morse, MA, Balogh, KK, Brendle, SA, Campbell, CA, Chen, MX, Furze, RC, Harada, IL, Holyer, ID, Kumar, U, Lee, K, Prinjha, RK, Rüdiger, M, Seal, JT, Taylor, S, Witherington, J & Christensen, ND 2018, 'BET bromodomain inhibitors show anti-papillomavirus activity in vitro and block CRPV wart growth in vivo', Antiviral Research, vol. 154, pp. 158-165. https://doi.org/10.1016/j.antiviral.2018.03.012

BET bromodomain inhibitors show anti-papillomavirus activity in vitro and block CRPV wart growth in vivo. / Morse, Mary A.; Balogh, Karla K.; Brendle, Sarah A.; Campbell, Colin A.; Chen, Mao X.; Furze, Rebecca C.; Harada, Isobel L.; Holyer, Ian D.; Kumar, Umesh; Lee, Kevin; Prinjha, Rab K.; Rüdiger, Martin; Seal, Jonathan T.; Taylor, Simon; Witherington, Jason; Christensen, Neil D.

In: Antiviral Research, Vol. 154, 06.2018, p. 158-165.

Research output: Contribution to journalArticle

TY - JOUR

T1 - BET bromodomain inhibitors show anti-papillomavirus activity in vitro and block CRPV wart growth in vivo

AU - Morse, Mary A.

AU - Balogh, Karla K.

AU - Brendle, Sarah A.

AU - Campbell, Colin A.

AU - Chen, Mao X.

AU - Furze, Rebecca C.

AU - Harada, Isobel L.

AU - Holyer, Ian D.

AU - Kumar, Umesh

AU - Lee, Kevin

AU - Prinjha, Rab K.

AU - Rüdiger, Martin

AU - Seal, Jonathan T.

AU - Taylor, Simon

AU - Witherington, Jason

AU - Christensen, Neil D.

PY - 2018/6

Y1 - 2018/6

N2 - The DNA papillomaviruses infect squamous epithelium and can cause persistent, benign and sometimes malignant hyperproliferative lesions. Effective antiviral drugs to treat human papillomavirus (HPV) infection are lacking and here we investigate the anti-papillomavirus activity of novel epigenetic targeting drugs, BET bromodomain inhibitors. Bromodomain and Extra-Terminal domain (BET) proteins are host proteins which regulate gene transcription, they bind acetylated lysine residues in histones and non-histone proteins via bromodomains, functioning as scaffold proteins in the formation of transcriptional complexes at gene regulatory regions. The BET protein BRD4 has been shown to be involved in the papillomavirus life cycle, as a co-factor for viral E2 and also mediating viral partitioning in some virus types. We set out to study the activity of small molecule BET bromodomain inhibitors in models of papillomavirus infection. Several BET inhibitors reduced HPV11 E1ˆE4 mRNA expression in vitro and topical therapeutic administration of an exemplar compound I-BET762, abrogated CRPV cutaneous wart growth in rabbits, demonstrating translation of anti-viral effects to efficacy in vivo. Additionally I-BET762 markedly reduced viability of HPV16 infected W12 cells compared to non-infected C33A cells. The molecular mechanism for the cytotoxicity to W12 cells is unknown but may be through blocking viral-dependent cell-survival factors. We conclude that these effects, across multiple papillomavirus types and in vivo, highlight the potential to target BET bromodomains to treat HPV infection.

AB - The DNA papillomaviruses infect squamous epithelium and can cause persistent, benign and sometimes malignant hyperproliferative lesions. Effective antiviral drugs to treat human papillomavirus (HPV) infection are lacking and here we investigate the anti-papillomavirus activity of novel epigenetic targeting drugs, BET bromodomain inhibitors. Bromodomain and Extra-Terminal domain (BET) proteins are host proteins which regulate gene transcription, they bind acetylated lysine residues in histones and non-histone proteins via bromodomains, functioning as scaffold proteins in the formation of transcriptional complexes at gene regulatory regions. The BET protein BRD4 has been shown to be involved in the papillomavirus life cycle, as a co-factor for viral E2 and also mediating viral partitioning in some virus types. We set out to study the activity of small molecule BET bromodomain inhibitors in models of papillomavirus infection. Several BET inhibitors reduced HPV11 E1ˆE4 mRNA expression in vitro and topical therapeutic administration of an exemplar compound I-BET762, abrogated CRPV cutaneous wart growth in rabbits, demonstrating translation of anti-viral effects to efficacy in vivo. Additionally I-BET762 markedly reduced viability of HPV16 infected W12 cells compared to non-infected C33A cells. The molecular mechanism for the cytotoxicity to W12 cells is unknown but may be through blocking viral-dependent cell-survival factors. We conclude that these effects, across multiple papillomavirus types and in vivo, highlight the potential to target BET bromodomains to treat HPV infection.

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