HBsAg mRNA degradation induced by a dihydroquinolizinone compound depends

newchinabok

https://www.sciencedirect.com/sc ... i/S0166354217305533

纠结哥哥

什么

antiHBVren

HBsAg mRNA degradation induced by a dihydroquinolizinone compound depends on the HBV posttranscriptional regulatory element
Author links open overlay panelTianlunZhouaTimothyBlockaFeiLiubAndrew S.KondratowiczcLirenSunaSiddharthaRawataJeffreyBransonaFangGuobHolly MicolochickSteuerbHongyanLiangaLaurenBaileybChrisMoorebXiaoheWangbAndyCuconattibMinGaobAmy C.H.LeecTroyHarasymcTimChiuc…Michael J.Sofiab
Show more
https://doi.org/10.1016/j.antiviral.2017.11.009Get rights and content
Highlights
•
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).


Abstract
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.

Previous article in issueNext article in issue
Keywords
Hepatitis B virusHBsAgPosttranscriptional regulatory elementDihydroquinolizinoneRNA degradation

antiHBVren

二氢喹吖嗪酮化合物诱导的HBsAg mRNA降解取决于HBV转录后调控元件

强调
•
一个小分子DHQ-1抑制HBV表面蛋白的生产和病毒复制。

•
DHQ-1增加核内HBV表面mRNA的转换。

•
DHQ-1诱导的病毒mRNA转换依赖于HBV转录后调控元件（HPRE）。


抽象
为了寻求靶向乙型肝炎病毒（HBV）感染的新型治疗剂，我们评估了在纳摩尔范围内减少组织培养物中病毒体和表面蛋白（HBsAg）产生的二氢喹喔啉酮化合物（DHQ-1）。该化合物也显示出广泛的HBV基因型覆盖率，但是对其他物种的DNA和RNA病毒小组无活性。在AAV-HBV小鼠模型中DHQ-1的口服给药导致血清HBsAg的显着降低，即在开始治疗后4天。在体外和体内实验中HBV标记的减少与包括前基因组RNA（pgRNA）和2.4 / 2.1kb HBsAg mRNA的病毒RNA的量减少有关。核运行和亚细胞分离实验表明，DHQ-1介导的HBV RNA减少是核内加速病毒RNA降解的结果，而不是抑制转录起始的结果。通过对HBsAg基因序列的诱变，我们发现通过DHQ-1诱导HBsAg mRNA衰减需要存在HBV转录后调节元件（HPRE），在HPREα亚单元的中心区域内具有109个核苷酸序列危急。总之，目前的研究表明，一个小分子可以降低HBV RNA的总体水平，特别是HBsAg mRNA和病毒表面蛋白。这可能揭示了一类新的HBV治疗药物的发展。