Ivermectin Inhibits HBV Entry into the Nucleus by Suppressing KPNA2
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...
| Main Authors: | , , , , , , , , , , , , , , , |
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MDPI AG
2022-11-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/14/11/2468 |
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| author | Anna Nakanishi Hiroki Okumura Tadahiro Hashita Aya Yamashita Yuka Nishimura Chihiro Watanabe Sakina Kamimura Sanae Hayashi Shuko Murakami Kyoko Ito Takahiro Iwao Akari Ikeda Tomoyasu Hirose Toshiaki Sunazuka Yasuhito Tanaka Tamihide Matsunaga |
| author_facet | Anna Nakanishi Hiroki Okumura Tadahiro Hashita Aya Yamashita Yuka Nishimura Chihiro Watanabe Sakina Kamimura Sanae Hayashi Shuko Murakami Kyoko Ito Takahiro Iwao Akari Ikeda Tomoyasu Hirose Toshiaki Sunazuka Yasuhito Tanaka Tamihide Matsunaga |
| author_sort | Anna Nakanishi |
| collection | DOAJ |
| description | 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<sup>+</sup> 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. |
| first_indexed | 2024-03-09T18:34:39Z |
| format | Article |
| id | doaj.art-c8cb069c76e847feb81b286bbed86399 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-09T18:34:39Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-c8cb069c76e847feb81b286bbed863992023-11-24T07:17:44ZengMDPI AGViruses1999-49152022-11-011411246810.3390/v14112468Ivermectin Inhibits HBV Entry into the Nucleus by Suppressing KPNA2Anna Nakanishi0Hiroki Okumura1Tadahiro Hashita2Aya Yamashita3Yuka Nishimura4Chihiro Watanabe5Sakina Kamimura6Sanae Hayashi7Shuko Murakami8Kyoko Ito9Takahiro Iwao10Akari Ikeda11Tomoyasu Hirose12Toshiaki Sunazuka13Yasuhito Tanaka14Tamihide Matsunaga15Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, JapanDepartment of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, JapanDepartment of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, JapanEducational Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, JapanEducational Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, JapanEducational Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, JapanEducational Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, JapanDepartment of Virology and Liver Unit, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, JapanDepartment of Virology and Liver Unit, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, JapanDepartment of Virology and Liver Unit, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, JapanDepartment of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, JapanŌmura Satoshi Memorial Institute, Graduate School of Infection Control Sciences, Kitasato University, Tokyo 108-8641, JapanŌmura Satoshi Memorial Institute, Graduate School of Infection Control Sciences, Kitasato University, Tokyo 108-8641, JapanŌmura Satoshi Memorial Institute, Graduate School of Infection Control Sciences, Kitasato University, Tokyo 108-8641, JapanDepartment of Virology and Liver Unit, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, JapanDepartment of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, JapanHepatitis 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<sup>+</sup> 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.https://www.mdpi.com/1999-4915/14/11/2468hepatitis B virusivermectinimportin α/βkaryopherin αhepatitis B surface antigenhepatitis B core protein |
| spellingShingle | Anna Nakanishi Hiroki Okumura Tadahiro Hashita Aya Yamashita Yuka Nishimura Chihiro Watanabe Sakina Kamimura Sanae Hayashi Shuko Murakami Kyoko Ito Takahiro Iwao Akari Ikeda Tomoyasu Hirose Toshiaki Sunazuka Yasuhito Tanaka Tamihide Matsunaga Ivermectin Inhibits HBV Entry into the Nucleus by Suppressing KPNA2 Viruses hepatitis B virus ivermectin importin α/β karyopherin α hepatitis B surface antigen hepatitis B core protein |
| title | Ivermectin Inhibits HBV Entry into the Nucleus by Suppressing KPNA2 |
| title_full | Ivermectin Inhibits HBV Entry into the Nucleus by Suppressing KPNA2 |
| title_fullStr | Ivermectin Inhibits HBV Entry into the Nucleus by Suppressing KPNA2 |
| title_full_unstemmed | Ivermectin Inhibits HBV Entry into the Nucleus by Suppressing KPNA2 |
| title_short | Ivermectin Inhibits HBV Entry into the Nucleus by Suppressing KPNA2 |
| title_sort | ivermectin inhibits hbv entry into the nucleus by suppressing kpna2 |
| topic | hepatitis B virus ivermectin importin α/β karyopherin α hepatitis B surface antigen hepatitis B core protein |
| url | https://www.mdpi.com/1999-4915/14/11/2468 |
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