The cyclophilin inhibitor CRV431 inhibits liver HBV DNA and HBsAg in transgenic mice.
Hepatitis B virus (HBV) infection is a major health burden worldwide with 240 million chronically infected individuals. Nucleos(t)ide analogs and interferons are the current standards of care due to their suppression of HBV replication, but the treatments rarely eradicate HBV from individuals. Simil...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2019-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0217433 |
| _version_ | 1797745318212665344 |
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| author | Philippe Gallay Daren Ure Michael Bobardt Udayan Chatterji James Ou Daniel Trepanier Robert Foster |
| author_facet | Philippe Gallay Daren Ure Michael Bobardt Udayan Chatterji James Ou Daniel Trepanier Robert Foster |
| author_sort | Philippe Gallay |
| collection | DOAJ |
| description | Hepatitis B virus (HBV) infection is a major health burden worldwide with 240 million chronically infected individuals. Nucleos(t)ide analogs and interferons are the current standards of care due to their suppression of HBV replication, but the treatments rarely eradicate HBV from individuals. Similar to current treatments for human immunodeficiency virus type-1 (HIV-1) and hepatitis C virus (HCV) patients, improved HBV therapies will require the combination of multiple drugs which target distinct steps of the HBV life cycle. In this study, we tested the potential of a cyclophilin inhibitor, CRV431, to affect HBV replication in transgenic mice. We found that oral treatment with CRV431 (50 mg/kg/day) for a period of 16 days significantly reduced liver HBV DNA levels and moderately decreased serum HBsAg levels. We observed an additive inhibitory effect on liver HBV DNA levels in mice treated with a combination of low doses of CRV431 (10 mg/kg/day) and the nucleotide prodrug, tenofovir exalidex (TXL), (5 mg/kg/day). No toxicity was observed in CRV431-treated mice. Although it is well known that CRV431 neutralizes the peptidyl-prolyl isomerase activity of cyclophilins, its anti-HBV mechanism(s) of action remains unknown. Nevertheless, this study provides the first demonstration of a beneficial effect of a cyclophilin inhibitor in vivo in an HBV transgenic mouse model. Altogether our data reveal the potential of CRV431 to be part of improved new therapies for HBV patients. |
| first_indexed | 2024-03-12T15:21:35Z |
| format | Article |
| id | doaj.art-3043b4e99c594fb88553cbc3157589bd |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-03-12T15:21:35Z |
| publishDate | 2019-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-3043b4e99c594fb88553cbc3157589bd2023-08-11T05:30:53ZengPublic Library of Science (PLoS)PLoS ONE1932-62032019-01-01146e021743310.1371/journal.pone.0217433The cyclophilin inhibitor CRV431 inhibits liver HBV DNA and HBsAg in transgenic mice.Philippe GallayDaren UreMichael BobardtUdayan ChatterjiJames OuDaniel TrepanierRobert FosterHepatitis B virus (HBV) infection is a major health burden worldwide with 240 million chronically infected individuals. Nucleos(t)ide analogs and interferons are the current standards of care due to their suppression of HBV replication, but the treatments rarely eradicate HBV from individuals. Similar to current treatments for human immunodeficiency virus type-1 (HIV-1) and hepatitis C virus (HCV) patients, improved HBV therapies will require the combination of multiple drugs which target distinct steps of the HBV life cycle. In this study, we tested the potential of a cyclophilin inhibitor, CRV431, to affect HBV replication in transgenic mice. We found that oral treatment with CRV431 (50 mg/kg/day) for a period of 16 days significantly reduced liver HBV DNA levels and moderately decreased serum HBsAg levels. We observed an additive inhibitory effect on liver HBV DNA levels in mice treated with a combination of low doses of CRV431 (10 mg/kg/day) and the nucleotide prodrug, tenofovir exalidex (TXL), (5 mg/kg/day). No toxicity was observed in CRV431-treated mice. Although it is well known that CRV431 neutralizes the peptidyl-prolyl isomerase activity of cyclophilins, its anti-HBV mechanism(s) of action remains unknown. Nevertheless, this study provides the first demonstration of a beneficial effect of a cyclophilin inhibitor in vivo in an HBV transgenic mouse model. Altogether our data reveal the potential of CRV431 to be part of improved new therapies for HBV patients.https://doi.org/10.1371/journal.pone.0217433 |
| spellingShingle | Philippe Gallay Daren Ure Michael Bobardt Udayan Chatterji James Ou Daniel Trepanier Robert Foster The cyclophilin inhibitor CRV431 inhibits liver HBV DNA and HBsAg in transgenic mice. PLoS ONE |
| title | The cyclophilin inhibitor CRV431 inhibits liver HBV DNA and HBsAg in transgenic mice. |
| title_full | The cyclophilin inhibitor CRV431 inhibits liver HBV DNA and HBsAg in transgenic mice. |
| title_fullStr | The cyclophilin inhibitor CRV431 inhibits liver HBV DNA and HBsAg in transgenic mice. |
| title_full_unstemmed | The cyclophilin inhibitor CRV431 inhibits liver HBV DNA and HBsAg in transgenic mice. |
| title_short | The cyclophilin inhibitor CRV431 inhibits liver HBV DNA and HBsAg in transgenic mice. |
| title_sort | cyclophilin inhibitor crv431 inhibits liver hbv dna and hbsag in transgenic mice |
| url | https://doi.org/10.1371/journal.pone.0217433 |
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