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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2019.01270

SIRT6 Inhibitor, OSS_128167 Restricts HBV Transcription and Replication through Targeting Transcription Factor PPARα

Hui Jiang1, Tao S. Cheng1, Hua J. Ren1, Bo H. Yu1, Qing Wang1, Ai-Long Huang1 and  Juan Chen1*
  • 1Chongqing Medical University, China

Hepatitis B virus (HBV) is a major public health threat and anti-HBV drugs are limited to nucleos(t)ide analogs (NAs) and pegylated interferon alpha (Peg-IFNα). Towards identifying an effective compound for HBV treatment is important to suppress and eradicate HBV. In this study, we explored the anti-viral effect of Sirtuin 6 (SIRT6) inhibitor, OSS_128167, in HBV transcription and replication. Firstly, we found that OSS_128167 could decrease the level of HBV core DNA and 3.5-Kb RNA in vitro. Furthermore, the level of HBV DNA and 3.5-Kb RNA were also markedly suppressed by OSS_128167 administration in HBV transgenic mice. In addition, we found that depletion of SIRT6 inhibited HBV transcription and replication in HepG2.2.15 and HBV-infected HepG2-NTCP cells, whereas overexpression of SIRT6 enhanced HBV transcription and replication. Importantly, the positive effect of SIRT6 overexpression on HBV transcription could be blocked by OSS_128167 treatment. Further mechanism studies showed that HBV core promoter was significantly activated by SIRT6 through upregulating peroxisome proliferator-activated receptors α (PPARα) expression. And ectopical expression of SIRT6 or PPARα relieved the restriction of HBV transcription mediated by OSS_128167. In summary, our results showed that OSS_128167 might serve as a potential antiviral agent for HBV therapy and SIRT6 played a pivotal role in HBV transcription and replication.

Keywords: OSS_128167, SIRT6, HBV, antiviral, Core promoter, PPARɑ

Received: 31 Jul 2019; Accepted: 04 Oct 2019.

Copyright: © 2019 Jiang, Cheng, Ren, Yu, Wang, Huang and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Juan Chen, Chongqing Medical University, Chongqing, 400016, China, chenjuan2014@cqmu.edu.cn