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

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.

Viral Manipulation of the Host Epigenome as a Driver of Virus-Induced Oncogenesis

“…Recently, it was reported that the BRD4 inhibitor JQ1 induces depletion of E6 in HPVinduced cervical cancer cells, increasing the sensitivity to cisplatin even in cisplatin-resistant cell lines. More importantly, this effect was observed to be specific to HPV-positive cells, while cisplatin-induced death in HPV-negative cells did not increase [380], as observed in a previous study that used I-BET762 [381]. Similarly, BRD4 inhibition can suppress the tumorigenic effect of HTLV1 Tax protein by inhibiting Nf-kB signaling.…”

Antiviral activity of green tea and black tea polyphenols in prophylaxis and treatment of COVID-19: A review

“… Virus Genome Conclusion Reference Porcine reproductive and respiratory syndrome virus (PRRSV) ssRNA EGCG effectively inhibits PRRSV infection and replication in porcine alveolar macrophages. It prevents MARC-145 cells from getting infected from PRRSV Ge et al. (2018) Hepatitis C virus (HCV) ssRNA EGCG prevents infection by inhibiting the entry of HCV into hepatoma cell lines and primary human hepatocytes thus Ciesek et al.…”

“…EGCG was found to inhibit Porcine reproductive and respiratory syndrome virus (PRRSV) infection irrespective of whether it was administered before or after infection; a concentration of 125 μM was enough to completely inhibit the infectivity of viral cells ( Ge et al., 2018 ). In Hepatitis C virus (HCV) infection, EGCG was found out to inhibit the infection by attaching to the target cell and preventing the spread of the infection to different cells ( Calland et al., 2012 ).…”

Safety and Efficacy of Bromodomain and Extra-Terminal Inhibitors for the Treatment of Hematological Malignancies and Solid Tumors: A Systematic Study of Clinical Trials

“…Since the discovery of the first two BET inhibitors GSK525762 and JQ1 ( Filippakopoulos et al, 2010 ; Nicodeme et al, 2010 ), a variety of new BET inhibitors have been developed. They serve a multitude of functions in various tumors, diabetes, chronic kidney failure, coronary artery disease, and other infectious diseases ( Gilan et al, 2020 ; Morse et al, 2018 ; Cochran et al, 2019 ). Their binding site is the BRD-acetyl binding pocket, hence blocking the binding of BET protein to the enhancers and promoters, mainly super-enhancers.…”