The retinoic acid receptor (RAR) α-specific agonist Am80 (tamibarotene) and other RAR agonists potently inhibit hepatitis B virus transcription from cccDNA

Nkongolo, Shirin; Nußbaum, Lea; Lempp, Florian A.; Wodrich, Harald; Urban, Stephan; Ni, Yi

doi:10.1016/j.antiviral.2019.04.009

Cited by 18 publications

(13 citation statements)

References 43 publications

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“…Nkongolo et al identified Tamibarotene (Am80) using another FDA-approved drug library and further compared Tamibarotene (RARα-specific) with other agonists: Tazarotene (RARβ -specific), Adapalene (RARγ-specific), and all-trans retinoic acid (pan-activity). Remarkably, Tamibarotene inhibits transcription selectively from cccDNA in primary hepatocytes but shows no effect on the transcription from integrants in HepG2.2.15 cells [ 118 ]. These studies suggested that RAR agonists targeting one subunit in the dimer would be sufficient to shut down gene transcription from cccDNA.…”

Section: Strategies Targeting Viral Transcriptionmentioning

confidence: 99%

Strategies to Inhibit Hepatitis B Virus at the Transcript Level

Brown

2021

Viruses

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Approximately 240 million people are chronically infected with hepatitis B virus (HBV), despite four decades of effective HBV vaccination. During chronic infection, HBV forms two distinct templates responsible for viral transcription: (1) episomal covalently closed circular (ccc)DNA and (2) host genome-integrated viral templates. Multiple ubiquitous and liver-specific transcription factors are recruited onto these templates and modulate viral gene transcription. This review details the latest developments in antivirals that inhibit HBV gene transcription or destabilize viral transcripts. Notably, nuclear receptor agonists exhibit potent inhibition of viral gene transcription from cccDNA. Small molecule inhibitors repress HBV X protein-mediated transcription from cccDNA, while small interfering RNAs and single-stranded oligonucleotides result in transcript degradation from both cccDNA and integrated templates. These antivirals mediate their effects by reducing viral transcripts abundance, some leading to a loss of surface antigen expression, and they can potentially be added to the arsenal of drugs with demonstrable anti-HBV activity. Thus, these candidates deserve special attention for future repurposing or further development as anti-HBV therapeutics.

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Section: Strategies Targeting Viral Transcriptionmentioning

confidence: 99%

Strategies to Inhibit Hepatitis B Virus at the Transcript Level

Brown

2021

Viruses

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“…ATRA belongs to retinoid family molecules and regulates a wide variety of physiological functions through its nuclear receptors, known as the classical retinoic acid receptors (RARs) and nonclassical retinoid X receptors (RXRs) (Duester et al, 2003; Mangelsdorf et al, 1990). To further verify and extend the effect of ATRA on secret levels of Cp in WD-Hep clinically-used retinoids, we employed 4 clinically-approved retinoid derivatives; Tazarotene and Am80 are RAR-selective retinoids (Chandraratna, 1996; Nkongolo et al, 2019), and Bexarotene and cis-4,7,10,13,16,19-Docosahexaenoic acid (DHA) are RXR-selective retinoids (Mounier et al, 2015; Zapata-Gonzalez et al, 2008). Effects of these four retinoids and ATRA on Cp secretion were further examined in WD-specific hepatocytes.…”

Section: Resultsmentioning

confidence: 99%

Retinoids rescue ceruloplasmin secretion and alleviate oxidative stress in Wilson’s disease-specific hepatocytes

Song

Takahashi

Zheng

et al. 2021

Preprint

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Wilson's disease (WD) is a copper metabolic disorder, which is caused by defective ATP7B function. Here, we have generated induced pluripotent stem cells (iPSCs) from WD patients carrying compound heterozygous mutations on ATP7B. ATP7B loss- and gain-of-functions were further manifested with ATP7B-deficient iPSCs and heterozygously-corrected R778L WD patient-derived iPSCs using CRISPR-Cas9-based gene editing. Transcriptome analysis identified abnormalities of retinoid signaling pathway and lipid metabolism in WD-specific hepatocytes. Although the expression level of ATP7B protein was variable among WD-specific hepatocytes, the expression and secretion of ceruloplasmin (Cp), which is a downstream copper carrier in plasma, were consistently decreased. Cp secretion-based drug screening identified all-trans retinoic acid (ATRA) as promising candidates for rescuing Cp secretion. ATRA also alleviated reactive oxygen species (ROS) production induced by lipid accumulation in WD-specific hepatocytes. Our patient-derived iPSC-based hepatic models provide potential therapeutics for liver steatosis in WD and other fatty liver diseases

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“…Nkongolo et al identified Tamibarotene (Am80) using another FDA approved drug library and further compared Tamibarotene (RAR-specific) with other agonists, Tazarotene (RAR/-specific), Adapalene (RAR-specific), all-trans retinoic acid (pan-activity). Remarkably, Tamibarotene inhibits transcription selectively from cccDNA in primary hepatocytes but shows no effect on the transcription from integrants in HepG2.2.15 cells [109]. These studies suggested that RAR agonists targeting one subunit in the dimer would be sufficient to shut down gene transcription from cccDNA.…”

Section: Retinoic Acid Receptor Agonistsmentioning

confidence: 94%

Strategies to Inhibit Hepatitis B Virus Gene Transcription

B¹,

Rjp²

2021

Preprint

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Approximately 240 million people are chronically infected with hepatitis B virus (HBV), despite four decades of an effective HBV vaccine. During chronic infection, HBV forms two distinct templates responsible for viral gene transcription: (1) episomal covalently closed circular (ccc)DNA and (2) host-genome integrated viral templates. Multiple ubiquitous and liver-specific transcription factors are recruited onto these templates and modulate viral gene transcription. This review details the latest developments in antivirals that inhibit HBV gene transcription, and their impact on the stability of viral transcripts. Notably, nuclear receptor agonists exhibit potent inhibition of viral gene transcription from cccDNA, small molecule inhibitors repress HBV X protein-mediated transcription from cccDNA and small interfering RNAs and single-stranded oligonucleotides result in transcript degradation from both cccDNA and integrant templates. These antivirals mediate their effects by reducing viral transcripts abundance, eventually leading to loss of surface antigen expression, and can potentially be added to the arsenal of drugs with demonstrable anti-HBV activity. Thus, these candidates deserve special attention for future repurposing or further development as anti-HBV therapeutics.

show abstract

The retinoic acid receptor (RAR) α-specific agonist Am80 (tamibarotene) and other RAR agonists potently inhibit hepatitis B virus transcription from cccDNA

Cited by 18 publications

References 43 publications

Strategies to Inhibit Hepatitis B Virus at the Transcript Level

Strategies to Inhibit Hepatitis B Virus at the Transcript Level

Retinoids rescue ceruloplasmin secretion and alleviate oxidative stress in Wilson’s disease-specific hepatocytes

Strategies to Inhibit Hepatitis B Virus Gene Transcription

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