HBsAg mRNA degradation induced by a dihydroquinolizinone compound depends on the HBV posttranscriptional regulatory element

HBsAg mRNA degradation induced by a dihydroquinolizinone compound depends on the HBV posttranscriptional regulatory element

In pursuit of novel therapeutics targeting the hepatitis B virus (HBV) infection, we evaluated a dihydroquinolizinone compound (DHQ-1) that in the nanomolar range reduced the production of virion and surface protein (HBsAg) in tissue culture. This compound also showed broad HBV genotype coverage, bu...

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Bibliographic Details
Published in:Antiviral research Vol. 149; pp. 191 - 201
Main Authors: Zhou, Tianlun, Block, Timothy, Liu, Fei, Kondratowicz, Andrew S., Sun, Liren, Rawat, Siddhartha, Branson, Jeffrey, Guo, Fang, Steuer, Holly Micolochick, Liang, Hongyan, Bailey, Lauren, Moore, Chris, Wang, Xiaohe, Cuconatti, Andy, Gao, Min, Lee, Amy C.H., Harasym, Troy, Chiu, Tim, Gotchev, Dimitar, Dorsey, Bruce, Rijnbrand, Rene, Sofia, Michael J.
Format: Journal Article
Language:English
Published: Netherlands Elsevier B.V 01-01-2018
Subjects:
Dihydroquinolizinone
HBsAg
Hepatitis B virus
Posttranscriptional regulatory element
RNA degradation
PRE
cccDNA
HCMV
DHBV
RNA degradation
DHQ
HRV
Flu
PHH
CHX
rcDNA
UTR
DNV-2
kb
NTCP
ACT-D
Hepatitis B virus
dlDNA
HBV
ssDNA
WNV
WHV
HBsAg
HSV
Posttranscriptional regulatory element
Dihydroquinolizinone
HIV
RSV
AAV
SLα
HCV
ELISA
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Summary:In pursuit of novel therapeutics targeting the hepatitis B virus (HBV) infection, we evaluated a dihydroquinolizinone compound (DHQ-1) that in the nanomolar range reduced the production of virion and surface protein (HBsAg) in tissue culture. This compound also showed broad HBV genotype coverage, but 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 significant reduction of serum HBsAg as soon as 4 days following the commencement of treatment. Reduction of HBV markers in both in vitro and in vivo experiments was related to the reduced amount of viral RNA including pre-genomic RNA (pgRNA) and 2.4/2.1 kb 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 of HBsAg gene sequences, we found induction of HBsAg mRNA decay by DHQ-1 required the presence of the HBV posttranscriptional 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 viral surface proteins. This may shed light on the development of a new class of HBV therapeutics. •A small molecule, DHQ-1, inhibited HBV surface protein production and viral replication.•DHQ-1 increased HBV surface mRNA turnover in the nucleus.•DHQ-1 induced viral mRNA turnover was dependent on the HBV Post-Transcriptional Regulatory Element (HPRE).
ISSN:0166-3542
1872-9096
DOI:10.1016/j.antiviral.2017.11.009