Antiviral Research
Antiviral Research
5 years ago

HBsAg mRNA degradation induced by dihydroquinolizinone molecule depends on HBV posttranscriptional regulatory element

In pursuit of novel therapeutics targeting the hepatitis B virus (HBV) infection, we evaluated a dihydroquinolizinone compound (DHQ-1) that possessed nanomolar activities against the production of virion and surface protein (HBsAg) in tissue culture. This compound also showed broad HBV genotype coverage and was inactive against a panel of DNA and RNA viruses of other species. Oral administration of DHQ-1 in the AAV-HBV mouse model resulted in a strong reduction of serum HBsAg as soon as 4 days following the commencement of treatment. Reduction of HBV marks in both in vitro and in vivo experiments was related to the down regulation of viral RNA including pre-genomic RNA (pgRNA) and 2.4/2.1Kb HBsAg mRNA. Nuclear run on and subcellular fractionation experiments indicated that DHQ-1 mediated HBV RNA reduction was the result of accelerated viral RNA degradation in the nucleus, rather than the consequence of inhibition of transcription initiation. Through mutagenesis analysis of HBsAg gene, we found induction of HBsAg mRNA decay by DHQ-1 required the presence of the HBV post transcriptional regulatory element (HPRE), with a 109 nucleotides sequence within the central region of the HPRE alpha sub-element, being the most critical. Taken together, the current study shows that a small molecule can reduce the overall levels of HBV RNA especially, the HBsAg mRNA and as such viral surface proteins, which may shed light on the development of a new class of HBV therapeutics.

Publisher URL: www.sciencedirect.com/science

DOI: S0166354217305533

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