匹莫苯丹通过抑制 HBV 启动子活性来抑制 HBV 转录和复制

StephenW

匹莫苯丹通过抑制 HBV 启动子活性来抑制 HBV 转录和复制
袁思雨 1 , 余海波 1 , 杨振 1 , 秦一萍 1 , 任继华 1 , 郑盛涛 1 , 方仁 1 , Betty Yuen Kwan Law 2 , Vincent Kam Wai Wong 2 , Jerome P L Ng 2 , Yu-Jiao Zhou 1 , Xin He 1 , Ming Tan 1 ,Zhen-Zhen Zhang 3 , Juuan Chen 1
隶属关系
隶属关系

    1
    重庆医科大学传染病分子生物学教育部重点实验室，重庆，中国。
    2
    中医药质量研究国家重点实验室，澳门科技大学，澳门，中国。
    3
    重庆市儿童感染与免疫重点实验室，儿童发育与障碍教育部重点实验室，国家儿童健康与障碍临床研究中心，重庆医科大学附属儿童医院感染科，重庆，中国。

    PMID：35721154 PMCID：PMC9204083 DOI：10.3389/fphar.2022.837115

抽象的

目前的抗HBV治疗策略依赖于干扰素和核苷（酸）类药物，具有功能治愈的局限性，在极少数患者中诱导乙型肝炎表面抗原（HBsAg）丢失。值得注意的是，HBsAg水平已被确立为评价药物疗效和预测疾病预后的准确指标，因此探索针对HBsAg的新型药物将具有重要意义。在此，通过从 FDA 批准的药物库中筛选 978 种化合物并确定每种药物对 HepG2.2.15 细胞上清液中 HBsAg 水平的抑制功能，我们发现匹莫苯 (Pim) 具有强大的抗病毒活性和相对较低的细胞毒性。 Pim 对 HBsAg 以及其他 HBV 标志物的抑制作用在 HBV 感染的细胞模型和 HBV 转基因小鼠中得到验证。从机理上讲，实时荧光定量 PCR 和双荧光素酶报告基因检测用于鉴定转录因子 CAAT 增强子结合蛋白 α (C/EBPα) 与 Pim 调控的 cccDNA 转录的部分相关性。这表明 Pim 是一种 HBV 转录抑制剂，通过抑制 HBV 启动子以降低 HBV RNA 水平和 HBsAg 产生。总之，Pim 被鉴定为 cccDNA 的转录抑制剂，从而在体外和体内抑制 HBsAg 和其他 HBV 复制中间体。该报告可能为开发新的抗HBV药物提供有希望的线索。

关键词：HBsAg；抗HBV药物；药物再利用；乙型肝炎病毒;匹莫苯。

版权所有 © 2022 Yuan, Yu, Yang, Qin, Ren, Cheng, Ren, Law, Wong, Ng, Zhou, He, Tan, Zhang and Chen。

StephenW

Pimobendan Inhibits HBV Transcription and Replication by Suppressing HBV Promoters Activity
Si-Yu Yuan  1 , Hai-Bo Yu  1 , Zhen Yang  1 , Yi-Ping Qin  1 , Ji-Hua Ren  1 , Sheng-Tao Cheng  1 , Fang Ren  1 , Betty Yuen Kwan Law  2 , Vincent Kam Wai Wong  2 , Jerome P L Ng  2 , Yu-Jiao Zhou  1 , Xin He  1 , Ming Tan  1 , Zhen-Zhen Zhang  3 , Juan Chen  1
Affiliations
Affiliations

    1
    The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.
    2
    State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao, China.
    3
    Chongqing Key Laboratory of Child Infection and Immunity, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Department of Infectious Diseases, The Children's Hospital of Chongqing Medical University, Chongqing, China.

    PMID: 35721154 PMCID: PMC9204083 DOI: 10.3389/fphar.2022.837115

Abstract

Current anti-HBV therapeutic strategy relies on interferon and nucleos(t)ide-type drugs with the limitation of functional cure, inducing hepatitis B surface antigen (HBsAg) loss in very few patients. Notably, the level of HBsAg has been established as an accurate indicator to evaluate the drug efficacy and predict the disease prognosis, thus exploring a novel drug targeting HBsAg will be of great significance. Herein, by screening 978 compounds from an FDA-approved drug library and determining the inhibitory function of each drug on HBsAg level in HepG2.2.15 cells supernatant, we identified that pimobendan (Pim) has a powerful antiviral activity with relatively low cytotoxicity. The inhibitory effect of Pim on HBsAg as well as other HBV markers was validated in HBV-infected cell models and HBV-transgenic mice. Mechanistically, real-time PCR and dual-luciferase reporter assay were applied to identify the partial correlation of transcription factor CAAT enhancer-binding protein α (C/EBPα) with the cccDNA transcription regulated by Pim. This indicates Pim is an inhibitor of HBV transcription through suppressing HBV promoters to reduce HBV RNAs levels and HBsAg production. In conclusion, Pim was identified to be a transcription inhibitor of cccDNA, thereby inhibiting HBsAg and other HBV replicative intermediates both in vitro and in vivo. This report may provide a promising lead for the development of new anti-HBV agent.

Keywords: HBsAg; anti-HBV agents; drug repurposing; hepatitis B virus; pimobendan.

Copyright © 2022 Yuan, Yu, Yang, Qin, Ren, Cheng, Ren, Law, Wong, Ng, Zhou, He, Tan, Zhang and Chen.

StephenW

https://www.frontiersin.org/arti ... har.2022.837115/pdf