烟酸类似物6-氨基烟酰胺，一种新型的乙型肝炎病毒复制和HBs

StephenW

EBioMedicine. 2019 Oct 31. pii: S2352-3964(19)30686-3. doi: 10.1016/j.ebiom.2019.10.022. [Epub ahead of print]
Niacin analogue, 6-Aminonicotinamide, a novel inhibitor of hepatitis B virus replication and HBsAg production.
Ren F1, Yang X1, Hu ZW1, Wong VKW2, Xu HY1, Ren JH1, Zhong S1, Jia XJ1, Jiang H1, Hu JL1, Cai XF1, Zhang WL1, Yao FL1, Yu HB1, Cheng ST1, Zhou HZ1, Huang AL1, Law BYK3, Chen J4.
Author information

1
    The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Room 617, College of Life Sciences Building, 1 YiXueYuan Road, YuZhong District, Chongqing 400016, China.
2
    State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Room 704a-02, Block H, Macau, China.
3
    State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Room 704a-02, Block H, Macau, China. Electronic address: [email protected].
4
    The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Room 617, College of Life Sciences Building, 1 YiXueYuan Road, YuZhong District, Chongqing 400016, China. Electronic address: [email protected].

Abstract
BACKGROUND:

Hepatitis B surface antigen (HBsAg) is one of the important clinical indexes for hepatitis B virus (HBV) infection diagnosis and sustained seroconversion of HBsAg is an indicator for functional cure. However, the level of HBsAg could not be reduced by interferons and nucleoside analogs effectively. Therefore, identification of a new drug targeting HBsAg is urgently needed.
METHODS:

In this study, 6-AN was screened out from 1500 compounds due to its low cytotoxicity and high antiviral activity. The effect of 6-AN on HBV was examined in HepAD38, HepG2-NTCP and PHHs cells. In addition, the antivirus effect of 6-AN was also identified in mouse model.
FINDINGS:

6-AN treatment resulted in a significant decrease of HBsAg and other viral markers both in vitro and in vivo. Furthermore, we found that 6-AN inhibited the activities of HBV SpI, SpII and core promoter by decreasing transcription factor PPARα, subsequently reduced HBV RNAs transcription and HBsAg production.
INTERPRETATION:

We have identified a novel small molecule to inhibit HBV core DNA, HBV RNAs, HBsAg production, as well as cccDNA to a minor degree both in vitro and in vivo. This study may shed light on the development of a novel class of anti-HBV agents.

Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.
KEYWORDS:

6-Aminonicotinamide (6-AN); Anti-HBV drugs; Hepatitis B surface antigen (HBsAg); Hepatitis B virus

PMID:
    31680002
DOI:
    10.1016/j.ebiom.2019.10.022

StephenW

EBioMedicine。 2019十月31. pii：S2352-3964（19）30686-3。 doi：10.1016 / j.ebiom.2019.10.022。 [Epub提前发布]
烟酸类似物6-氨基烟酰胺，一种新型的乙型肝炎病毒复制和HBsAg产生抑制剂。
任F1，杨X1，胡ZW1，黄VKW2，徐HY1，任JH1，钟S1，贾XJ1，姜H1，胡JL1，蔡XF1，张WL1，姚FL1，余HB1，程ST1，周HZ1，黄AL1 ，法律BYK3，陈J4。
作者信息

1个
重庆医科大学第二附属医院病毒性肝炎研究所传染病科，中国教育部指定的传染病分子生物学重点实验室，重庆市渝中区益学园路1号生命科学学院楼617室重庆400016
2
澳门科技大学中药质量研究国家重点实验室，中国澳门H座704a-02室。
3
澳门科技大学中药质量研究国家重点实验室，中国澳门H座704a-02室。电子地址：[email protected]。
4
重庆医科大学第二附属医院病毒性肝炎研究所传染病科，中国教育部指定的传染病分子生物学重点实验室，重庆市渝中区益学园路1号生命科学学院楼617室重庆400016电子地址：[email protected]。

抽象
背景：

乙型肝炎表面抗原（HBsAg）是诊断乙型肝炎病毒（HBV）的重要临床指标之一，并且持续的血清转化是功能性治愈的指标。然而，干扰素和核苷类似物无法降低HBsAg的水平。迫切需要鉴定靶向HBsAg的新药。
方法：

在这项研究中，由于其低细胞毒性和高抗病毒活性，从1500种化合物中筛选出6-AN。在HepAD38，HepG2-NTCP和PHHs细胞中检查了6-AN对HBV的作用。另外，还在小鼠模型中鉴定了6-AN的抗病毒作用。
发现：

6-AN治疗导致体内外的HBsAg和其他病毒标记物显着降低。此外，我们发现6-AN通过降低转录因子PPARα抑制HBV SpI，SpII和核心启动子的活性，随后降低了HBV RNAs转录和HBsAg的产生。
解释：

我们已经确定了一种新颖的小分子，可以在体外和体内抑制HBV核心DNA，HBV RNA，HBsAg以及cccDNA的生成。这项研究可能为新型抗乙肝病毒药物的开发提供启示。

版权所有©2019 The Authors。由Elsevier B.V.发布。保留所有权利。
关键字：

6-氨基烟酰胺（6-AN）；抗乙肝病毒药物；乙型肝炎表面抗原（HBsAg）；乙肝病毒

PMID：
31680002
DOI：
10.1016 / j.ebiom.2019.10.022

StephenW

https://www.ebiomedicine.com/article/S2352-3964(19)30686-3/pdf