Canocapavir Is a Novel Capsid Assembly Modulator Inducing a Conformational Change of the Linker Region of HBV Core Protein

被引:2
|
作者
Zheng, Yuan [1 ,2 ]
Yang, Le [1 ,2 ]
Yu, Lin [1 ,2 ]
Zhu, Yuanfei [1 ,2 ]
Wu, Yang [1 ]
Zhang, Zhijun [3 ]
Xia, Tian [3 ]
Deng, Qiang [1 ,2 ]
机构
[1] Fudan Univ, Sch Basic Med Sci, Shanghai Frontiers Sci Ctr Pathogen Microorganisms, Key Lab Med Mol Virol MOE,NHC,CAMS, Shanghai 200032, Peoples R China
[2] Shanghai Inst Infect Dis & Biosecur, Shanghai 200032, Peoples R China
[3] Shanghai Zhimeng Biopharm Inc, 1976 Gaoke Middle Rd,Suite A-302, Shanghai 201210, Peoples R China
来源
VIRUSES-BASEL | 2023年 / 15卷 / 05期
关键词
hepatitis B virus; hepatitis B virus core protein; core protein allosteric modulator; capsid assembly; viral particle egress; allosteric effect; VIRUS-REPLICATION; INHIBITION; DOMAIN;
D O I
10.3390/v15051195
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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.
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页数:18
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  • [1] Novel HBV capsid assembly modulator inhibits pregenomic RNA encapsidation by accelerating capsid assembly kinetics and disrupting core protein dephosphorylation
    Bassit, Leda
    Verma, Kiran
    Ono, Suzane Kioko
    Cox, Bryan
    Amblard, Franck
    Schinazi, Raymond F.
    [J]. JOURNAL OF HEPATOLOGY, 2019, 70 (01) : E457 - E457
  • [2] Interaction between nucleophosmin and HBV core protein increases HBV capsid assembly
    Jeong, Heewon
    Cho, Min-Hyung
    Park, Sung-Gyoo
    Jung, Guhung
    [J]. FEBS LETTERS, 2014, 588 (06) : 851 - 858
  • [3] The interdomain linker region of HIV-1 capsid protein is a critical determinant of proper core assembly and stability
    Jiang, Jiyang
    Ablan, Sherimay D.
    Derebail, Suchitra
    Hercik, Kamil
    Soheilian, Ferri
    Thomas, James A.
    Tang, Shixing
    Hewlett, Indira
    Nagashima, Kunio
    Gorelick, Robert J.
    Freed, Eric O.
    Levin, Judith G.
    [J]. VIROLOGY, 2011, 421 (02) : 253 - 265
  • [4] Discovery of SHR5133, a Highly Potent and Novel HBV Capsid Assembly Modulator
    Li, Xin
    Zhang, Zhigao
    Chen, Yang
    Wang, Bin
    Yang, Guimei
    Xu, Xiangbin
    Yechao, Baihui
    Bai, Dongdong
    Feng, Binqiang
    Mao, Yuchang
    Feng, Jun
    Bai, Chang
    He, Feng
    Tao, Weikang
    [J]. ACS MEDICINAL CHEMISTRY LETTERS, 2022, 13 (03): : 507 - 512
  • [5] A Disulfide in HBV Core Protein Dimer Allosterically Modifies Capsid Assembly and Stability
    Selzer, Lisa
    Katen, Sarah
    Zlotnick, Adam
    [J]. BIOPHYSICAL JOURNAL, 2014, 106 (02) : 60A - 60A
  • [6] Class A capsid assembly modulator apoptotic elimination of hepatocytes with high HBV core antigen level in vivo is dependent on de novo core protein translation
    Berke, Jan Martin
    Tan, Ying
    Sauviller, Sarah
    Wu, Dai-tze
    Zhang, Ke
    Conceicao-Neto, Nadia
    Blazquez Moreno, Alfonso
    Kong, Desheng
    Kukolj, George
    Li, Chris
    Zhu, Ren
    Najera, Isabel
    Pauwels, Frederik
    [J]. JOURNAL OF VIROLOGY, 2024, 98 (03)
  • [7] A novel hepatitis B virus capsid assembly modulator QL-007 inhibits HBV replication and infection through altering capsid assembly
    Xi, Jingyuan
    Gu, Zhiqiang
    Sun, Chunyan
    Chen, Zimin
    Zhang, Ting
    Chen, Ran
    Liu, Tianyu
    Liao, Hao
    Zou, Jun
    Yang, Danli
    Xu, Qiang
    Wang, Jie
    Wei, Guochao
    Cheng, Zhe
    Lu, Fengmin
    Chen, Xiangmei
    [J]. ANTIVIRAL RESEARCH, 2023, 218
  • [8] Discovery and development of a novel, class I Core protein Assembly Modulator (CpAM) for the treatment of chronic HBV infection
    Zhu, Wei
    [J]. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2019, 258
  • [9] Allosteric conformational changes of human HBV core protein transform its assembly
    Chuang Liu
    Guizhen Fan
    Zhao Wang
    Hong-Song Chen
    Chang-Cheng Yin
    [J]. Scientific Reports, 7
  • [10] Allosteric conformational changes of human HBV core protein transform its assembly
    Liu, Chuang
    Fan, Guizhen
    Wang, Zhao
    Chen, Hong-Song
    Yin, Chang-Cheng
    [J]. SCIENTIFIC REPORTS, 2017, 7