Canocapavir Is a Novel Capsid Assembly Modulator Inducing a Conformational Change of the Linker Region of HBV Core Protein
Canocapavir is a novel antiviral agent with characteristics of core protein allosteric modulators (CpAMs) that is currently in a phase II clinical trial for treatment of hepatitis B virus (HBV) infection. Herein, we show that Canocapavir prevented the encapsidation of HBV pregenomic RNA and increase...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-05-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/15/5/1195 |
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| author | Yuan Zheng Le Yang Lin Yu Yuanfei Zhu Yang Wu Zhijun Zhang Tian Xia Qiang Deng |
| author_facet | Yuan Zheng Le Yang Lin Yu Yuanfei Zhu Yang Wu Zhijun Zhang Tian Xia Qiang Deng |
| author_sort | Yuan Zheng |
| collection | DOAJ |
| description | Canocapavir is a novel antiviral agent with characteristics of core protein allosteric modulators (CpAMs) that is currently in a phase II clinical trial for treatment of hepatitis B virus (HBV) infection. Herein, we show that Canocapavir prevented the encapsidation of HBV pregenomic RNA and increased the accumulation of cytoplasmic empty capsids, presumably by targeting the hydrophobic pocket at the dimer-dimer interface of HBV core protein (HBc). Canocapavir treatment markedly reduced the egress of naked capsids, which could be reversed by Alix overexpression through a mechanism other than direct association of Alix with HBc. Moreover, Canocapavir interfered with the interaction between HBc and HBV large surface protein, resulting in diminished production of empty virions. Of particular note, Canocapavir induced a conformational change of capsids, with the C-terminus of HBc linker region fully exposed on the exterior of capsids. We posit that the allosteric effect may have great importance in the anti-HBV activity of Canocapavir, given the emerging virological significance of HBc linker region. In support of this notion, the mutation at HBc V124W typically recapitulated the conformational change of the empty capsid with aberrant cytoplasmic accumulation. Collectively, our results indicate Canocapavir as a mechanistically distinct type of CpAMs against HBV infection. |
| first_indexed | 2024-03-11T03:14:16Z |
| format | Article |
| id | doaj.art-422bc702e5f349a3b4efbd07962dc886 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-11T03:14:16Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-422bc702e5f349a3b4efbd07962dc8862023-11-18T03:40:20ZengMDPI AGViruses1999-49152023-05-01155119510.3390/v15051195Canocapavir Is a Novel Capsid Assembly Modulator Inducing a Conformational Change of the Linker Region of HBV Core ProteinYuan Zheng0Le Yang1Lin Yu2Yuanfei Zhu3Yang Wu4Zhijun Zhang5Tian Xia6Qiang Deng7Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Fudan University, Shanghai 200032, ChinaKey Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Fudan University, Shanghai 200032, ChinaKey Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Fudan University, Shanghai 200032, ChinaKey Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Fudan University, Shanghai 200032, ChinaKey Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Fudan University, Shanghai 200032, ChinaShanghai Zhimeng Biopharma, Inc., 1976 Gaoke Middle Road, Suite A-302, Pudong District, Shanghai 201210, ChinaShanghai Zhimeng Biopharma, Inc., 1976 Gaoke Middle Road, Suite A-302, Pudong District, Shanghai 201210, ChinaKey Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Fudan University, Shanghai 200032, ChinaCanocapavir is a novel antiviral agent with characteristics of core protein allosteric modulators (CpAMs) that is currently in a phase II clinical trial for treatment of hepatitis B virus (HBV) infection. Herein, we show that Canocapavir prevented the encapsidation of HBV pregenomic RNA and increased the accumulation of cytoplasmic empty capsids, presumably by targeting the hydrophobic pocket at the dimer-dimer interface of HBV core protein (HBc). Canocapavir treatment markedly reduced the egress of naked capsids, which could be reversed by Alix overexpression through a mechanism other than direct association of Alix with HBc. Moreover, Canocapavir interfered with the interaction between HBc and HBV large surface protein, resulting in diminished production of empty virions. Of particular note, Canocapavir induced a conformational change of capsids, with the C-terminus of HBc linker region fully exposed on the exterior of capsids. We posit that the allosteric effect may have great importance in the anti-HBV activity of Canocapavir, given the emerging virological significance of HBc linker region. In support of this notion, the mutation at HBc V124W typically recapitulated the conformational change of the empty capsid with aberrant cytoplasmic accumulation. Collectively, our results indicate Canocapavir as a mechanistically distinct type of CpAMs against HBV infection.https://www.mdpi.com/1999-4915/15/5/1195hepatitis B virushepatitis B virus core proteincore protein allosteric modulatorcapsid assemblyviral particle egressallosteric effect |
| spellingShingle | Yuan Zheng Le Yang Lin Yu Yuanfei Zhu Yang Wu Zhijun Zhang Tian Xia Qiang Deng Canocapavir Is a Novel Capsid Assembly Modulator Inducing a Conformational Change of the Linker Region of HBV Core Protein Viruses hepatitis B virus hepatitis B virus core protein core protein allosteric modulator capsid assembly viral particle egress allosteric effect |
| title | Canocapavir Is a Novel Capsid Assembly Modulator Inducing a Conformational Change of the Linker Region of HBV Core Protein |
| title_full | Canocapavir Is a Novel Capsid Assembly Modulator Inducing a Conformational Change of the Linker Region of HBV Core Protein |
| title_fullStr | Canocapavir Is a Novel Capsid Assembly Modulator Inducing a Conformational Change of the Linker Region of HBV Core Protein |
| title_full_unstemmed | Canocapavir Is a Novel Capsid Assembly Modulator Inducing a Conformational Change of the Linker Region of HBV Core Protein |
| title_short | Canocapavir Is a Novel Capsid Assembly Modulator Inducing a Conformational Change of the Linker Region of HBV Core Protein |
| title_sort | canocapavir is a novel capsid assembly modulator inducing a conformational change of the linker region of hbv core protein |
| topic | hepatitis B virus hepatitis B virus core protein core protein allosteric modulator capsid assembly viral particle egress allosteric effect |
| url | https://www.mdpi.com/1999-4915/15/5/1195 |
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