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CN 22-1108/R
Volume 38 Issue 8
Aug.  2022
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Article Navigation >  Journal of Clinical Hepatology  > 2022  >  38(8): 1726-1732

Mechanism of action, clinical research and development, and application prospect of hepatitis B virus core protein allosteric modulators

DOI: 10.3969/j.issn.1001-5256.2022.08.005
  • 1.

    Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China

  • 2.

    Baruch S. Blumberg Institute, Doylestown, Pennsylvania 18902, USA

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  • Corresponding author: LIU Hui, liuhui5215@126.com(ORCID: 0000-0002-6537-8093)
  • Received Date: 2022-05-29
  • Accepted Date: 2022-07-04
  • Published Date: 2022-08-20
    Abstract
  • Hepatitis B virus (HBV) infection is the main pathogenic factor for chronic hepatitis, and if it is not treated timely and effectively, it may have the risk of developing into end-stage liver diseases such as liver cirrhosis and hepatocellular carcinoma. Neither of the two types of antiviral drugs currently used in clinical practice can completely inhibit viral replication or eliminate viral transcriptional template, which means that covalently closed circular DNA (cccDNA) exists in infected liver cells for a long time, and thus patients with chronic hepatitis B require long-term or even lifelong medication. Therefore, it is of great importance to develop novel anti-HBV drugs. Core protein allosteric modulators (CpAM) are a type of novel anti-HBV drugs and can interfere with HBV nucleocapsid assembly and inhibit the depolymerization of mature nucleocapsid, the formation of cccDNA, and the biogenesis and secretion of HBeAg. CpAM have a great potential in clinical application since they act on various links of viral replication. This article reviews the function of CpAM target protein-core protein, the classification, action targets, and anti-HBV mechanism of CpAM, and the current research status, further development, and application prospect of CpAM.

     

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  • [1]
    SEEGER C, MASON WS. Molecular biology of hepatitis B virus infection[J]. Virology, 2015, 479-480: 672-686. DOI: 10.1016/j.virol.2015.02.031.
    [2]
    YAN H, ZHONG G, XU G, et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus[J]. Elife, 2012, 1: e00049. DOI: 10.7554/eLife.00049.
    [3]
    NASSAL M. HBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis B[J]. Gut, 2015, 64(12): 1972-1984. DOI: 10.1136/gutjnl-2015-309809.
    [4]
    VENKATAKRISHNAN B, ZLOTNICK A. The structural biology of hepatitis b virus: form and function[J]. Annu Rev Virol, 2016, 3(1): 429-451. DOI: 10.1146/annurev-virology-110615-042238.
    [5]
    SCHMITZ A, SCHWARZ A, FOSS M, et al. Nucleoporin 153 arrests the nuclear import of hepatitis B virus capsids in the nuclear basket[J]. PLoS Pathog, 2010, 6(1): e1000741. DOI: 10.1371/journal.ppat.1000741.
    [6]
    HU Z, BAN H, ZHENG H, et al. Protein phosphatase 1 catalyzes HBV core protein dephosphorylation and is co-packaged with viral pregenomic RNA into nucleocapsids[J]. PLoS Pathog, 2020, 16(7): e1008669. DOI: 10.1371/journal.ppat.1008669.
    [7]
    ZHAO Q, HU Z, CHENG J, et al. Hepatitis B virus core protein dephosphorylation occurs during pregenomic RNA encapsidation[J]. J Virol, 2018, 92(13). DOI: 10.1128/JVI.02139-17.
    [8]
    NING X, NGUYEN D, MENTZER L, et al. Secretion of genome-free hepatitis B virus-single strand blocking model for virion morphogenesis of para-retrovirus[J]. PLoS Pathog, 2011, 7(9): e1002255. DOI: 10.1371/journal.ppat.1002255.
    [9]
    LECOQ L, WANG S, DUJARDIN M, et al. A pocket-factor-triggered conformational switch in the hepatitis B virus capsid[J]. Proc Natl Acad Sci U S A, 2021, 118(17). DOI: 10.1073/pnas.2022464118.
    [10]
    LIU K, LUCKENBAUGH L, NING X, et al. Multiple roles of core protein linker in hepatitis B virus replication[J]. PLoS Pathog, 2018, 14(5): e1007085. DOI: 10.1371/journal.ppat.1007085.
    [11]
    TUTTLEMAN JS, POURCEL C, SUMMERS J. Formation of the pool of covalently closed circular viral DNA in hepadnavirus-infected cells[J]. Cell, 1986, 47(3): 451-460. DOI: 10.1016/0092-8674(86)90602-1.
    [12]
    HU J, TANG L, CHENG J, et al. Hepatitis B virus nucleocapsid uncoating: biological consequences and regulation by cellular nucleases[J]. Emerg Microbes Infect, 2021, 10(1): 852-864. DOI: 10.1080/22221751.2021.1919034.
    [13]
    BOCK CT, SCHWINN S, LOCARNINI S, et al. Structural organization of the hepatitis B virus minichromosome[J]. J Mol Biol, 2001, 307(1): 183-196. DOI: 10.1006/jmbi.2000.4481.
    [14]
    LUCIFORA J, XIA Y, REISINGER F, et al. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA[J]. Science, 2014, 343(6176): 1221-1228. DOI: 10.1126/science.1243462.
    [15]
    XIA Y, LUCIFORA J, REISINGER F, et al. Virology. Response to comment on "Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA"[J]. Science, 2014, 344(6189): 1237. DOI: 10.1126/science.1254083.
    [16]
    CHABROLLES H, AUCLAIR H, VEGNA S, et al. Hepatitis B virus core protein nuclear interactome identifies SRSF10 as a host RNA-binding protein restricting HBV RNA production[J]. PLoS Pathog, 2020, 16(11): e1008593. DOI: 10.1371/journal.ppat.1008593.
    [17]
    KING RW, LADNER SK, MILLER TJ, et al. Inhibition of human hepatitis B virus replication by AT-61, a phenylpropenamide derivative, alone and in combination with (-)beta-L-2', 3'-dideoxy-3'-thiacytidine[J]. Antimicrob Agents Chemother, 1998, 42(12): 3179-3186. DOI: 10.1128/AAC.42.12.3179.
    [18]
    DERES K, SCHRÖDER CH, PAESSENS A, et al. Inhibition of hepatitis B virus replication by drug-induced depletion of nucleocapsids[J]. Science, 2003, 299(5608): 893-896. DOI: 10.1126/science.1077215.
    [19]
    CAMPAGNA MR, LIU F, MAO R, et al. Sulfamoylbenzamide derivatives inhibit the assembly of hepatitis B virus nucleocapsids[J]. J Virol, 2013, 87(12): 6931-6942. DOI: 10.1128/JVI.00582-13.
    [20]
    BOURNE CR, FINN MG, ZLOTNICK A. Global structural changes in hepatitis B virus capsids induced by the assembly effector HAP1[J]. J Virol, 2006, 80(22): 11055-11061. DOI: 10.1128/JVI.00933-06.
    [21]
    KANG JA, KIM S, PARK M, et al. Ciclopirox inhibits hepatitis B virus secretion by blocking capsid assembly[J]. Nat Commun, 2019, 10(1): 2184. DOI: 10.1038/s41467-019-10200-5.
    [22]
    LAHLALI T, BERKE JM, VERGAUWEN K, et al. Novel potent capsid assembly modulators regulate multiple steps of the hepatitis B virus life cycle[J]. Antimicrob Agents Chemother, 2018, 62(10): e00835-18. DOI: 10.1128/AAC.00835-18.
    [23]
    GHAEMI Z, GRUEBELE M, TAJKHORSHID E. Molecular mechanism of capsid disassembly in hepatitis B virus[J]. Proc Natl Acad Sci U S A, 2021, 118(36): e2102530118. DOI: 10.1073/pnas.2102530118.
    [24]
    VENKATAKRISHNAN B, KATEN SP, FRANCIS S, et al. Hepatitis B virus capsids have diverse structural responses to small-molecule ligands bound to the heteroaryldihydropyrimidine pocket[J]. J Virol, 2016, 90(8): 3994-4004. DOI: 10.1128/JVI.03058-15.
    [25]
    KATEN SP, CHIRAPU SR, FINN MG, et al. Trapping of hepatitis B virus capsid assembly intermediates by phenylpropenamide assembly accelerators[J]. ACS Chem Biol, 2010, 5(12): 1125-1136. DOI: 10.1021/cb100275b.
    [26]
    ZHOU Z, HU T, ZHOU X, et al. Heteroaryldihydropyrimidine (HAP) and sulfamoylbenzamide (SBA) inhibit hepatitis B virus replication by different molecular mechanisms[J]. Sci Rep, 2017, 7: 42374. DOI: 10.1038/srep42374.
    [27]
    KATEN SP, TAN Z, CHIRAPU SR, et al. Assembly-directed antivirals differentially bind quasiequivalent pockets to modify hepatitis B virus capsid tertiary and quaternary structure[J]. Structure, 2013, 21(8): 1406-1416. DOI: 10.1016/j.str.2013.06.013.
    [28]
    SCHLICKSUP CJ, WANG JC, FRANCIS S, et al. Hepatitis B virus core protein allosteric modulators can distort and disrupt intact capsids[J]. Elife, 2018, 7: e31473. DOI: 10.7554/eLife.31473.
    [29]
    SCHLICKSUP CJ, LAUGHLIN P, DUNKELBARGER S, et al. Local stabilization of subunit-subunit contacts causes global destabilization of hepatitis B virus capsids[J]. ACS Chem Biol, 2020, 15(6): 1708-1717. DOI: 10.1021/acschembio.0c00320.
    [30]
    KO C, BESTER R, ZHOU X, et al. A new role for capsid assembly modulators to target mature hepatitis B virus capsids and prevent virus infection[J]. Antimicrob Agents Chemother, 2019, 64(1): e01440-19. DOI: 10.1128/AAC.01440-19.
    [31]
    GUO F, ZHAO Q, SHERAZ M, et al. HBV core protein allosteric modulators differentially alter cccDNA biosynthesis from de novo infection and intracellular amplification pathways[J]. PLoS Pathog, 2017, 13(9): e1006658. DOI: 10.1371/journal.ppat.1006658.
    [32]
    HUANG Q, CAI D, YAN R, et al. Preclinical profile and characterization of the hepatitis B virus core protein inhibitor ABI-H0731[J]. Antimicrob Agents Chemother, 2020, 64(11). DOI: 10.1128/AAC.01463-20.
    [33]
    LIU H, CHENG J, VISWANATHAN U, et al. Amino acid residues at core protein dimer-dimer interface modulate multiple steps of hepatitis B virus replication and HBeAg biogenesis[J]. PLoS Pathog, 2021, 17(11): e1010057. DOI: 10.1371/journal.ppat.1010057.
    [34]
    YAN Z, WU D, HU H, et al. Direct inhibition of hepatitis B e antigen by core protein allosteric modulator[J]. Hepatology, 2019, 70(1): 11-24. DOI: 10.1002/hep.30514.
    [35]
    LIN J, YIN L, XU XZ, et al. Bay41-4109-induced aberrant polymers of hepatitis b capsid proteins are removed via STUB1-promoted p62-mediated macroautophagy[J]. PLoS Pathog, 2022, 18(1): e1010204. DOI: 10.1371/journal.ppat.1010204.
    [36]
    SELZER L, ZLOTNICK A. Assembly and release of hepatitis B virus[J]. Cold Spring Harb Perspect Med, 2015, 5(12): a021394. DOI: 10.1101/cshperspect.a021394.
    [37]
    DIMATTIA MA, WATTS NR, STAHL SJ, et al. Antigenic switching of hepatitis B virus by alternative dimerization of the capsid protein[J]. Structure, 2013, 21(1): 133-142. DOI: 10.1016/j.str.2012.10.017.
    [38]
    VISWANATHAN U, MANI N, HU Z, et al. Targeting the multifunctional HBV core protein as a potential cure for chronic hepatitis B[J]. Antiviral Res, 2020, 182: 104917. DOI: 10.1016/j.antiviral.2020.104917.
    [39]
    YUEN MF, GANE EJ, KIM DJ, et al. Antiviral activity, safety, and pharmacokinetics of capsid assembly modulator NVR 3-778 in patients with chronic HBV infection[J]. Gastroenterology, 2019, 156(5): 1392-1403. e7. DOI: 10.1053/j.gastro.2018.12.023.
    [40]
    ZHAO N, JIA B, ZHAO H, et al. A first-in-human trial of GLS4, a novel inhibitor of hepatitis B virus capsid assembly, following single- and multiple-ascending-oral-dose studies with or without ritonavir in healthy adult volunteers[J]. Antimicrob Agents Chemother, 2019, 64(1): e01686-19. DOI: 10.1128/AAC.01686-19.
    [41]
    MANI N, COLE AG, PHELPS JR, et al. Preclinical characterization of AB-506, an inhibitor of HBV replication targeting the viral core protein[J]. Antiviral Res, 2022, 197: 105211. DOI: 10.1016/j.antiviral.2021.105211.
    [42]
    YUEN M, BERLIBA E, SUKEEPAISARNJAROEN W, et al. Safety, tolerability, pharmacokinetics (PK), and antiviral activity of the capsid inhibitor (CI) AB-506 in healthy subjects (HS) and chronic hepatitis B (CHB) subjects[J]. Hepatology, 2019, 70(6): 1492A-1493A.
    [43]
    LEE A, THI EP, ARDZINSKI A, et al. Hepatitis B virus core protein variants observed in a first-in-human placebo-controlled study of a core protein inhibitor[J]. J Hepatol, 2020, 73: S833.
    [44]
    YUEN MF, AGARWAL K, GANE EJ, et al. Safety, pharmacokinetics, and antiviral effects of ABI-H0731, a hepatitis B virus core inhibitor: a randomised, placebo-controlled phase 1 trial[J]. Lancet Gastroenterol Hepatol, 2020, 5(2): 152-166. DOI: 10.1016/S2468-1253(19)30346-2.
    [45]
    YUEN MF, AGARWAL K, MA X, et al. Safety and efficacy of vebicorvir in virologically suppressed patients with chronic hepatitis B virus infection[J]. J Hepatol, 2022. DOI: 10.1016/j.jhep.2022.04.005. [Online ahead of print]
    [46]
    SULKOWSKI MS, AGARWAL K, MA X, et al. Safety and efficacy of vebicorvir administered with entecavir in treatment-naïve patients with chronic hepatitis B virus infection[J]. J Hepatol, 2022. DOI: 10.1016/j.jhep.2022.05.027. [Online ahead of print]
    [47]
    GANE E, SULKOWSKI M, MA XL, et al. Viral response and safety following discontinuation of treatment with the core inhibitor vebicorvir and a nucleos(t)ide reverse transcriptase inhibitor in patients with HBeAg positive or negative chronic hepatitis B virus infection(PO-482)[C]// EASL Digital International Liver Conference, June 23-26, 2021.
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