伊维菌素通过抑制 KPNA2 抑制 HBV 进入细胞核

StephenW

伊维菌素通过抑制 KPNA2 抑制 HBV 进入细胞核
中西安娜 1 , 奥村博树 1 , 桥田忠宏 1 2 , 山下绫 2 , 西村由香 2 , 渡边千寻 2 , 神村咲菜 2 , 林早苗 3 4 , 村上秀子 3 , 伊藤恭子 3 , 岩尾贵弘 1 2 , 池田明里 5 , Tomoyasu Hirose 5 , Toshiaki Sunazuka 5 , Yasuhito Tanaka 3 4 , Tamihide Matsunaga 1 2
隶属关系
隶属关系

    1个
    名古屋市立大学药学研究生院临床药学系，日本名古屋 467-8603。
    2个
    名古屋市立大学药学院临床药学教育研究中心，日本名古屋 467-8603。
    3个
    名古屋市立大学医学研究生院病毒学和肝脏科，日本名古屋 467-8601。
    4
    熊本大学胃肠病学和肝病学系，日本熊本 860-8556。
    5
    大村聪纪念研究所，北里大学感染控制科学研究科，东京 108-8641，日本。

    PMID：36366568 DOI：10.3390/v14112468

抽象的

乙型肝炎病毒 (HBV) 特异性感染人类肝细胞并增加肝硬化和肝癌的风险。目前，核酸类似物是HBV感染引起的慢性肝炎的主要治疗药物。虽然核酸类似物可以通过抑制HBV逆转录酶来消除HBV DNA，但它们不能导致共价闭合环状DNA（cccDNA）和乙型肝炎表面抗原（HBsAg）的负转化。在这项研究中，我们揭示了抗丝虫药物伊维菌素通过与核酸类似物恩替卡韦或 Na+ 牛磺胆酸盐共转运多肽介导的进入抑制剂环孢菌素 A 不同的机制抑制 HBV 的产生。伊维菌素降低了几种 HBV 标志物的水平，包括 HBsAg、在HBV感染的人肝细胞癌细胞（HepG2-hNTCP-C4细胞）和人源化小鼠肝细胞（PXB肝细胞）中。此外，伊维菌素显着降低了 HepG2-hNTCP-C4 细胞核中 HBV 核心蛋白和核转运蛋白核转运蛋白 α2 (KPNA2) 的表达。此外，KPNA1-6 的消耗抑制了 cccDNA 的产生。这些结果表明，KPNA1-6 参与了 HBV 的核输入，并且伊维菌素通过抑制 KPNA2 抑制了 HBV 的核输入。这项研究证明了伊维菌素作为乙型肝炎新疗法的潜力。

关键词：乙肝核心蛋白；乙型肝炎表面抗原；乙型肝炎病毒;输入α/β；伊维菌素；核转运蛋白α；核定位信号；核移植。

StephenW

Ivermectin Inhibits HBV Entry into the Nucleus by Suppressing KPNA2
Anna Nakanishi  1 , Hiroki Okumura  1 , Tadahiro Hashita  1   2 , Aya Yamashita  2 , Yuka Nishimura  2 , Chihiro Watanabe  2 , Sakina Kamimura  2 , Sanae Hayashi  3   4 , Shuko Murakami  3 , Kyoko Ito  3 , Takahiro Iwao  1   2 , Akari Ikeda  5 , Tomoyasu Hirose  5 , Toshiaki Sunazuka  5 , Yasuhito Tanaka  3   4 , Tamihide Matsunaga  1   2
Affiliations
Affiliations

    1
    Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan.
    2
    Educational Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan.
    3
    Department of Virology and Liver Unit, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan.
    4
    Department of Gastroenterology and Hepatology, Kumamoto University, Kumamoto 860-8556, Japan.
    5
    Ōmura Satoshi Memorial Institute, Graduate School of Infection Control Sciences, Kitasato University, Tokyo 108-8641, Japan.

    PMID: 36366568 DOI: 10.3390/v14112468

Abstract

Hepatitis B virus (HBV) specifically infects human hepatocytes and increases the risks of cirrhosis and liver cancer. Currently, nucleic acid analogs are the main therapeutics for chronic hepatitis caused by HBV infection. Although nucleic acid analogs can eliminate HBV DNA by inhibiting HBV reverse transcriptase, they cannot lead to negative conversion of covalently closed circular DNA (cccDNA) and hepatitis B surface antigen (HBsAg). In this study, we revealed that the antifilarial drug ivermectin suppresses HBV production by a different mechanism from the nucleic acid analog entecavir or Na+ taurocholate co-transporting polypeptide-mediated entry inhibitor cyclosporin A. Ivermectin reduced the levels of several HBV markers, including HBsAg, in HBV-infected human hepatocellular carcinoma cells (HepG2-hNTCP-C4 cells) and humanized mouse hepatocytes (PXB hepatocytes). In addition, ivermectin significantly decreased the expression of HBV core protein and the nuclear transporter karyopherin α2 (KPNA2) in the nuclei of HepG2-hNTCP-C4 cells. Furthermore, depletion of KPNA1-6 suppressed the production of cccDNA. These results suggest that KPNA1-6 is involved in the nuclear import of HBV and that ivermectin suppresses the nuclear import of HBV by inhibiting KPNA2. This study demonstrates the potential of ivermectin as a novel treatment for hepatitis B.

Keywords: hepatitis B core protein; hepatitis B surface antigen; hepatitis B virus; importin α/β; ivermectin; karyopherin α; nuclear localization signal; nuclear transfer.

StephenW

https://www.mdpi.com/1999-4915/14/11/2468/pdf?version=1667911951