通过药物再利用筛选鉴定维甲酸受体激动剂作为有效的乙型

StephenW

Antimicrob Agents Chemother. 2018 Sep 17. pii: AAC.00465-18. doi: 10.1128/AAC.00465-18. [Epub ahead of print]
Identification of Retinoic Acid Receptor Agonists as Potent Hepatitis B Virus Inhibitors via a Drug Repurposing Screen.
Li B1,2, Wang Y1, Shen F1,2, Wu M1, Li Y1, Fang Z1, Ye J1, Wang L2, Gao L3, Yuan Z4, Chen J4.
Author information

1
    Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.
2
    Roche Innovation Center Shanghai, China.
3
    Roche Innovation Center Shanghai, China [email protected].
4
    Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China [email protected] [email protected].

Abstract

Currently available therapies for chronic hepatitis B virus (HBV) infection can efficiently reduce viremia, but induce hepatitis B surface antigen (HBsAg) loss in a very few patients and do not much affect the viral covalently closed circular DNA (cccDNA). To discover new agents with complementary anti-HBV effects, we performed a drug repurposing screen of 1,018 Food and Drug Administration (FDA)-approved compounds using HBV-infected primary human hepatocytes (PHH). Several compounds belonging to the family of retinoic acid receptor (RAR) agonists were identified that reduced HBsAg levels in a dose-dependent manner without significant cytotoxicity. Among them, Tazarotene exhibited the most potent anti-HBV effect with an IC50 for HBsAg of less than 30 nM in PHH. The inhibitory effect was also observed in HBV-infected dHepaRG models, but not in HepG2.215 cells, and HBV genotype A to D were similarly inhibited. Tazarotene was further demonstrated to repress HBV cccDNA transcription, as determined by the levels of HBV cccDNA, RNAs and the activation of HBV promoters. Moreover, RNA-sequence analysis showed that Tazarotene did not induce an interferon response, but altered the expression of a number of genes associated with RAR and metabolic pathways. Inhibition of RARβ, but not RARα, by specific antagonist significantly attenuated the anti-HBV activity of Tazarotene, suggesting Tazarotene inhibits HBV in part through RARβ. Finally, a synergistic effect of Tazarotene and Entecavir on HBV-DNA levels was observed. Therefore, RAR agonists as represented by Tazarotene were identified as potential novel anti-HBV agents.

PMID:
    30224536
DOI:
    10.1128/AAC.00465-18

StephenW

抗微生物剂Chemother。 2018年9月17日.pii：AAC.00465-18。 doi：10.1128 / AAC.00465-18。 [提前打印]
通过药物再利用筛选鉴定维甲酸受体激动剂作为有效的乙型肝炎病毒抑制剂。
Li B1,2，Wang Y1，Shen F1,2，Wu M1，Li Y1，Fang Z1，Ye J1，Wang L2，Gao L3，Yuan Z4，Chen J4。
作者信息

1
    复旦大学上海医学院基础医学院医学分子病毒学重点实验室，上海
2
    罗氏创新中心中国上海。
3
    罗氏创新中心中国上海[email protected]。
4
    复旦大学上海医学院基础医学院医学分子病毒学重点实验室，上海[email protected] [email protected]。

抽象

目前可用于慢性乙型肝炎病毒（HBV）感染的疗法可以有效地减少病毒血症，但是在极少数患者中诱导乙型肝炎表面抗原（HBsAg）丧失并且对病毒共价闭合环状DNA（cccDNA）没有太大影响。为了发现具有互补抗HBV作用的新药物，我们使用HBV感染的原代人肝细胞（PHH）进行了1,018种食品和药物管理局（FDA）批准的化合物的药物再利用筛选。鉴定了属于视黄酸受体（RAR）激动剂家族的几种化合物，其以剂量依赖性方式降低HBsAg水平而没有显着的细胞毒性。其中，他扎罗汀显示出最有效的抗HBV效应，PHH中HBsAg的IC50小于30nM。在HBV感染的dHepaRG模型中也观察到抑制作用，但在HepG2.215细胞中未观察到抑制作用，并且HBV基因型A至D被类似地抑制。进一步证明他扎罗汀可抑制HBV cccDNA转录，这可通过HBV cccDNA，RNA和HBV启动子的激活来确定。此外，RNA序列分析显示他扎罗汀不诱导干扰素反应，但改变了与RAR和代谢途径相关的许多基因的表达。特异性拮抗剂对RARβ的抑制，但不抑制RARα，显着减弱他扎罗汀的抗HBV活性，表明他扎罗汀部分通过RARβ抑制HBV。最后，观察到他扎罗汀和恩替卡韦对HBV-DNA水平的协同作用。因此，以他扎罗汀为代表的RAR激动剂被鉴定为潜在的新型抗HBV剂。

结论：
    30224536
DOI：
    10.1128 / AAC.00465-18

齐欢畅

好思路啊

齐欢畅

阿的平

齐欢畅

可否再研究一下，确实有抑制乙肝病毒的作用