Strategies to Inhibit Hepatitis B Virus at the Transcript Level

• Published in: Viruses Vol. 13; no. 7; p. 1327
• Main Authors: Qu, Bingqian, Brown, Richard J. P.
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 09.07.2021; MDPI
• Subjects: Antigens; Antiviral agents; chronic hepatitis B; Chronic illnesses; Chronic infection; Circular DNA; covalently closed circular DNA; DNA polymerase; DNA repair; Drug development; Drug resistance; Genomes; Hepatitis B; Hepatitis C; Infections; Liver; nuclear receptor; Oligonucleotides; Proteins; Review; transcription factor; Transcription factors; transcriptional inhibitor; Vaccination; viral integration; Viruses
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v13071327

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.