請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/99964完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳培哲 | zh_TW |
| dc.contributor.advisor | Pei-Jer Chen | en |
| dc.contributor.author | 陳冠宏 | zh_TW |
| dc.contributor.author | Guan-Hung Chen | en |
| dc.date.accessioned | 2025-09-22T16:09:54Z | - |
| dc.date.available | 2025-09-23 | - |
| dc.date.copyright | 2025-09-22 | - |
| dc.date.issued | 2025 | - |
| dc.date.submitted | 2025-07-28 | - |
| dc.identifier.citation | 1. P. J. Easterbrook et al., WHO 2024 hepatitis B guidelines: an opportunity to transform care. The Lancet Gastroenterology & Hepatology 9, 493-495 (2024).
2. J. H. MacLachlan, B. C. Cowie, Hepatitis B virus epidemiology. Cold Spring Harb Perspect Med 5, a021410 (2015). 3. M.-F. Yuen et al., Hepatitis B virus infection. Nature Reviews Disease Primers 4, 18035 (2018). 4. M. Sunbul, Hepatitis B virus genotypes: global distribution and clinical importance. World J Gastroenterol 20, 5427-5434 (2014). 5. T. J. Liang, Hepatitis B: the virus and disease. Hepatology 49, S13-21 (2009). 6. N. Chai et al., Properties of subviral particles of hepatitis B virus. J Virol 82, 7812-7817 (2008). 7. S. Tsukuda, K. Watashi, Hepatitis B virus biology and life cycle. Antiviral Research 182, 104925 (2020). 8. K.-C. Luk et al., More DNA and RNA of HBV SP1 splice variants are detected in genotypes B and C at low viral replication. Scientific Reports 11, 23838 (2021). 9. Y. Xia, H. Guo, Hepatitis B virus cccDNA: Formation, regulation and therapeutic potential. Antiviral Research 180, 104824 (2020). 10. F. Zhao et al., The Functions of Hepatitis B Virus Encoding Proteins: Viral Persistence and Liver Pathogenesis. Front Immunol 12, 691766 (2021). 11. J. K. Jeong, G. S. Yoon, W. S. Ryu, Evidence that the 5'-end cap structure is essential for encapsidation of hepatitis B virus pregenomic RNA. J Virol 74, 5502-5508 (2000). 12. J. Hu, C. Seeger, Hepadnavirus Genome Replication and Persistence. Cold Spring Harb Perspect Med 5, a021386 (2015). 13. L. Selzer, A. Zlotnick, Assembly and Release of Hepatitis B Virus. Cold Spring Harb Perspect Med 5 (2015). 14. U. Viswanathan et al., Targeting the multifunctional HBV core protein as a potential cure for chronic hepatitis B. Antiviral Res 182, 104917 (2020). 15. Q. Zhao et al., Hepatitis B Virus Core Protein Dephosphorylation Occurs during Pregenomic RNA Encapsidation. J Virol 92 (2018). 16. A. Diab, A. Foca, F. Zoulim, D. Durantel, O. Andrisani, The diverse functions of the hepatitis B core/capsid protein (HBc) in the viral life cycle: Implications for the development of HBc-targeting antivirals. Antiviral Res 149, 211-220 (2018). 17. S. A. Wynne, R. A. Crowther, A. G. W. Leslie, The Crystal Structure of the Human Hepatitis B Virus Capsid. Molecular Cell 3, 771-780 (1999). 18. A. Zlotnick et al., Core protein: A pleiotropic keystone in the HBV lifecycle. Antiviral Research 121, 82-93 (2015). 19. J. Hu, D. Flores, D. Toft, X. Wang, D. Nguyen, Requirement of heat shock protein 90 for human hepatitis B virus reverse transcriptase function. J Virol 78, 13122-13131 (2004). 20. H. Daub et al., Identification of SRPK1 and SRPK2 as the major cellular protein kinases phosphorylating hepatitis B virus core protein. J Virol 76, 8124-8137 (2002). 21. M. Kann, W. H. Gerlich, Effect of core protein phosphorylation by protein kinase C on encapsidation of RNA within core particles of hepatitis B virus. J Virol 68, 7993-8000 (1994). 22. X. Ning et al., Common and Distinct Capsid and Surface Protein Requirements for Secretion of Complete and Genome-Free Hepatitis B Virions. J Virol 92 (2018). 23. C.-Y. Chung et al., Major HBV splice variant encoding a novel protein important for infection. Journal of Hepatology 80, 858-867 (2024). 24. K. Deres et al., Inhibition of Hepatitis B Virus Replication by Drug-Induced Depletion of Nucleocapsids. Science 299, 893-896 (2003). 25. C. N. Chang et al., Deoxycytidine deaminase-resistant stereoisomer is the active form of (+/-)-2',3'-dideoxy-3'-thiacytidine in the inhibition of hepatitis B virus replication. Journal of Biological Chemistry 267, 13938-13942 (1992). 26. P. Marcellin et al., Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 348, 808-816 (2003). 27. K. P. Fischer, K. S. Gutfreund, D. L. Tyrrell, Lamivudine resistance in hepatitis B: mechanisms and clinical implications. Drug Resistance Updates 4, 118-128 (2001). 28. Y. F. Liaw et al., 2-Year GLOBE trial results: telbivudine Is superior to lamivudine in patients with chronic hepatitis B. Gastroenterology 136, 486-495 (2009). 29. E. Tsai, Review of Current and Potential Treatments for Chronic Hepatitis B Virus Infection. Gastroenterol Hepatol (N Y) 17, 367-376 (2021). 30. M. Sherman et al., Entecavir therapy for lamivudine-refractory chronic hepatitis B: improved virologic, biochemical, and serology outcomes through 96 weeks. Hepatology 48, 99-108 (2008). 31. D. Babusis, T. K. Phan, W. A. Lee, W. J. Watkins, A. S. Ray, Mechanism for effective lymphoid cell and tissue loading following oral administration of nucleotide prodrug GS-7340. Mol Pharm 10, 459-466 (2013). 32. F. McNab, K. Mayer-Barber, A. Sher, A. Wack, A. O'Garra, Type I interferons in infectious disease. Nature Reviews Immunology 15, 87-103 (2015). 33. H. B. Greenberg et al., Effect of human leukocyte interferon on hepatitis B virus infection in patients with chronic active hepatitis. N Engl J Med 295, 517-522 (1976). 34. H. L. Janssen et al., Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet 365, 123-129 (2005). 35. J. Chen et al., Functional Comparison of Interferon‐α Subtypes Reveals Potent Hepatitis B Virus Suppression by a Concerted Action of Interferon‐α and Interferon‐γ Signaling. Hepatology 73, 486-502 (2021). 36. P. Tropberger et al., Mapping of histone modifications in episomal HBV cccDNA uncovers an unusual chromatin organization amenable to epigenetic manipulation. Proceedings of the National Academy of Sciences 112, E5715-E5724 (2015). 37. J. Cheng et al., Interferon Alpha Induces Multiple Cellular Proteins That Coordinately Suppress Hepadnaviral Covalently Closed Circular DNA Transcription. J Virol 94 (2020). 38. Y. Liu et al., Interferon-inducible ribonuclease ISG20 inhibits hepatitis B virus replication through directly binding to the epsilon stem-loop structure of viral RNA. PLoS Pathog 13, e1006296 (2017). 39. Y. X. Wang et al., Interferon-inducible MX2 is a host restriction factor of hepatitis B virus replication. J Hepatol 72, 865-876 (2020). 40. Y. Wang et al., SAMD4 family members suppress human hepatitis B virus by directly binding to the Smaug recognition region of viral RNA. Cell Mol Immunol 18, 1032-1044 (2021). 41. M. Sajid et al., The Functional and Antiviral Activity of Interferon Alpha-Inducible IFI6 Against Hepatitis B Virus Replication and Gene Expression. Front Immunol 12, 634937 (2021). 42. T. Li et al., ADAR1 Stimulation by IFN-α Downregulates the Expression of MAVS via RNA Editing to Regulate the Anti-HBV Response. Mol Ther 29, 1335-1348 (2021). 43. H. Imam, G. W. Kim, S. A. Mir, M. Khan, A. Siddiqui, Interferon-stimulated gene 20 (ISG20) selectively degrades N6-methyladenosine modified Hepatitis B Virus transcripts. PLoS Pathog 16, e1008338 (2020). 44. G. Tan et al., Identification of TRIM14 as a Type I IFN-Stimulated Gene Controlling Hepatitis B Virus Replication by Targeting HBx. Front Immunol 9, 1872 (2018). 45. J. Hao et al., Inhibition of alpha interferon (IFN-α)-induced microRNA-122 negatively affects the anti-hepatitis B virus efficiency of IFN-α. J Virol 87, 137-147 (2013). 46. A. G. Hovanessian, J. Justesen, The human 2'-5'oligoadenylate synthetase family: unique interferon-inducible enzymes catalyzing 2'-5' instead of 3'-5' phosphodiester bond formation. Biochimie 89, 779-788 (2007). 47. F. Wieland Stefan, G. Guidotti Luca, V. Chisari Francis, Intrahepatic Induction of Alpha/Beta Interferon Eliminates Viral RNA-Containing Capsids in Hepatitis B Virus Transgenic Mice. Journal of Virology 74, 4165-4173 (2000). 48. S. F. Wieland, A. Eustaquio, C. Whitten-Bauer, B. Boyd, F. V. Chisari, Interferon prevents formation of replication-competent hepatitis B virus RNA-containing nucleocapsids. Proc Natl Acad Sci U S A 102, 9913-9917 (2005). 49. C. Xu et al., Interferons Accelerate Decay of Replication-Competent Nucleocapsids of Hepatitis B Virus. Journal of Virology 84, 9332-9340 (2010). 50. G. Ligat, E. R. Verrier, M. Nassal, T. F. Baumert, Hepatitis B virus-host interactions and novel targets for viral cure. Curr Opin Virol 49, 41-51 (2021). 51. R. B. Perni et al., Phenylpropenamide derivatives as inhibitors of hepatitis B virus replication. Bioorg Med Chem Lett 10, 2687-2690 (2000). 52. R. W. King 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. Antimicrob Agents Chemother 42, 3179-3186 (1998). 53. O. Weber et al., Inhibition of human hepatitis B virus (HBV) by a novel non-nucleosidic compound in a transgenic mouse model. Antiviral Research 54, 69-78 (2002). 54. V. Taverniti et al., Capsid Assembly Modulators as Antiviral Agents against HBV: Molecular Mechanisms and Clinical Perspectives. Journal of Clinical Medicine 11, 1349 (2022). 55. H. Vanrusselt et al., Novel non-HAP class A HBV capsid assembly modulators have distinct in vitro and in vivo profiles. J Virol 97, e0072223 (2023). 56. L. Lecoq et al., Molecular elucidation of drug-induced abnormal assemblies of the hepatitis B virus capsid protein by solid-state NMR. Nature Communications 14, 471 (2023). 57. L. Ruan, J. A. Hadden, A. Zlotnick, Assembly properties of hepatitis B virus core protein mutants correlate with their resistance to assembly-directed antivirals. Journal of virology 92, 10.1128/jvi. 01082-01018 (2018). 58. G. Billioud, C. Pichoud, G. Puerstinger, J. Neyts, F. Zoulim, The main hepatitis B virus (HBV) mutants resistant to nucleoside analogs are susceptible in vitro to non-nucleoside inhibitors of HBV replication. Antiviral Res 92, 271-276 (2011). 59. W. E. t. Delaney et al., Phenylpropenamide derivatives AT-61 and AT-130 inhibit replication of wild-type and lamivudine-resistant strains of hepatitis B virus in vitro. Antimicrob Agents Chemother 46, 3057-3060 (2002). 60. J. M. Berke et al., Antiviral profiling of the capsid assembly modulator BAY41-4109 on full-length HBV genotype A-H clinical isolates and core site-directed mutants in vitro. Antiviral Res 144, 205-215 (2017). 61. D. Burdette et al., Characterization of a Novel Capsid Assembly Modulator for the Treatment of Chronic Hepatitis B Virus Infection. Antimicrobial Agents and Chemotherapy 67, e01348-01322 (2023). 62. Z. Yan et al., Direct Inhibition of Hepatitis B e Antigen by Core Protein Allosteric Modulator. Hepatology 70, 11-24 (2019). 63. V. Rat et al., BAY 41-4109-mediated aggregation of assembled and misassembled HBV capsids in cells revealed by electron microscopy. Antiviral Research 169, 104557 (2019). 64. A. Corcuera et al., Novel non-heteroarylpyrimidine (HAP) capsid assembly modifiers have a different mode of action from HAPs in vitro. Antiviral Research 158, 135-142 (2018). 65. S. P. Katen, S. R. Chirapu, M. G. Finn, A. Zlotnick, Trapping of Hepatitis B Virus Capsid Assembly Intermediates by Phenylpropenamide Assembly Accelerators. ACS Chemical Biology 5, 1125-1136 (2010). 66. N. Brezillon et al., Antiviral activity of Bay 41-4109 on hepatitis B virus in humanized Alb-uPA/SCID mice. PLoS One 6, e25096 (2011). 67. J. Lin et al., Bay41-4109-induced aberrant polymers of hepatitis b capsid proteins are removed via STUB1-promoted p62-mediated macroautophagy. PLoS Pathog 18, e1010204 (2022). 68. X. Y. Wang et al., In vitro inhibition of HBV replication by a novel compound, GLS4, and its efficacy against adefovir-dipivoxil-resistant HBV mutations. Antivir Ther 17, 793-803 (2012). 69. G. Wu et al., Preclinical characterization of GLS4, an inhibitor of hepatitis B virus core particle assembly. Antimicrob Agents Chemother 57, 5344-5354 (2013). 70. Z. Sun et al., Physiologically-based pharmacokinetic modeling predicts the drug interaction potential of GLS4 in co-administered with ritonavir. CPT Pharmacometrics Syst Pharmacol 13, 1503-1512 (2024). 71. N. Zhao 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. Antimicrob Agents Chemother 64 (2019). 72. D. B. Kum et al., Class A capsid assembly modulator RG7907 clears HBV-infected hepatocytes through core-dependent hepatocyte death and proliferation. Hepatology 78 (2023). 73. X. Zhou et al., In vitro and in vivo antiviral characterization of RO7049389, a novel small molecule capsid assembly modulator for the treatment of chronic hepatitis B. Journal of Hepatology 68, S770 (2018). 74. W. Zhang et al., Discovery of Linvencorvir (RG7907), a Hepatitis B Virus Core Protein Allosteric Modulator, for the Treatment of Chronic HBV Infection. Journal of Medicinal Chemistry 66, 4253-4270 (2023). 75. Y. Debing et al., ALG-005398 is a potent non-HAP class I HBV capsid assembly modulator that strongly reduces HBsAg levels in vivo. Hepatology 74, 502A-503A (2021). 76. H. Vanrusselt et al., TOP-358-YI Non-HAP CAM-A ALG-006746 and ALG-006780 induce rapid HBsAg reductions in AAV-HBV mice and have favorable pharmacokinetic profiles. Journal of Hepatology 80, S728 (2024). 77. Q. Huang et al., Preclinical Profile and Characterization of the Hepatitis B Virus Core Protein Inhibitor ABI-H0731. Antimicrobial Agents and Chemotherapy 64, 10.1128/aac.01463-01420 (2020). 78. J. J. Feld et al., The phenylpropenamide derivative AT-130 blocks HBV replication at the level of viral RNA packaging. Antiviral Research 76, 168-177 (2007). 79. K. Klumpp et al., Efficacy of NVR 3-778, Alone and In Combination With Pegylated Interferon, vs Entecavir In uPA/SCID Mice With Humanized Livers and HBV Infection. Gastroenterology 154, 652-662.e658 (2018). 80. E. J. Gane et al., Phase 1a Safety and Pharmacokinetics of NVR 3-778, a Potential First-In-Class HBV Core Inhibitor: LB-19. Hepatology 60, 1279A (2014). 81. A. M. Lam et al., Preclinical Characterization of NVR 3-778, a First-in-Class Capsid Assembly Modulator against Hepatitis B Virus. Antimicrobial Agents and Chemotherapy 63, 10.1128/aac.01734-01718 (2019). 82. M. F. Yuen et al., Antiviral Activity, Safety, and Pharmacokinetics of Capsid Assembly Modulator NVR 3-778 in Patients with Chronic HBV Infection. Gastroenterology 156, 1392-1403.e1397 (2019). 83. A. G. Cole et al., Rational Design, Synthesis, and Structure–Activity Relationship of a Novel Isoquinolinone-Based Series of HBV Capsid Assembly Modulators Leading to the Identification of Clinical Candidate AB-836. Journal of Medicinal Chemistry 67, 16773-16795 (2024). 84. A. M. Lam et al., Preclinical and clinical antiviral characterization of AB-836, a potent capsid assembly modulator against hepatitis B virus. Antiviral Research 231, 106010 (2024). 85. B. Nijampatnam, D. C. Liotta, Recent advances in the development of HBV capsid assembly modulators. Current Opinion in Chemical Biology 50, 73-79 (2019). 86. K. Vandyck et al. (2019) Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B. (Google Patents). 87. F. Amblard et al., Novel Hepatitis B Virus Capsid Assembly Modulator Induces Potent Antiviral Responses In Vitro and in Humanized Mice. Antimicrob Agents Chemother 64 (2020). 88. Q. Zhang et al. (2020) Best-In-Class Preclinical Characteristics of Alg-000184, A Prodrug of The Capsid Assembly Modulator Alg-001075 for the Treatment of Chronic Hepatitis B. in The Liver Meeting Digital Experience™ (AASLD). 89. Y. Debing et al., Capsid assembly modulator ALG-000111 and its prodrug ALG-000286 display excellent in vitro and in vivo antiviral activity. Cell 500, 4 (2021). 90. H. Zhang et al., Antiviral Activity and Pharmacokinetics of the Hepatitis B Virus (HBV) Capsid Assembly Modulator GLS4 in Patients With Chronic HBV Infection. Clinical Infectious Diseases 73, 175-182 (2020). 91. M. Zhang et al., Efficacy and safety of GLS4 with entecavir vs entecavir alone in chronic hepatitis B patients: A multicenter clinical trial. Journal of Infection 90, 106446 (2025). 92. J. Hou et al., Efficacy, safety, and pharmacokinetics of capsid assembly modulator linvencorvir plus standard of care in chronic hepatitis B patients. Clin Mol Hepatol 30, 191-205 (2024). 93. M.-F. Yuen et al., Safety, pharmacokinetics, and antiviral effects of ABI-H0731, a hepatitis B virus core inhibitor: a randomised, placebo-controlled phase 1 trial. The Lancet Gastroenterology & Hepatology 5, 152-166 (2020). 94. M. S. Sulkowski et al., Safety and efficacy of vebicorvir administered with entecavir in treatment-naïve patients with chronic hepatitis B virus infection. Journal of Hepatology 77, 1265-1275 (2022). 95. F. Zoulim et al., JNJ-56136379, an HBV Capsid Assembly Modulator, Is Well-Tolerated and Has Antiviral Activity in a Phase 1 Study of Patients With Chronic Infection. Gastroenterology 159, 521-533.e529 (2020). 96. M. F. Yuen et al., Efficacy and safety of the siRNA JNJ-73763989 and the capsid assembly modulator JNJ-56136379 (bersacapavir) with nucleos(t)ide analogues for the treatment of chronic hepatitis B virus infection (REEF-1): a multicentre, double-blind, active-controlled, randomised, phase 2b trial. Lancet Gastroenterol Hepatol 8, 790-802 (2023). 97. Y. Zheng et al., Canocapavir Is a Novel Capsid Assembly Modulator Inducing a Conformational Change of the Linker Region of HBV Core Protein. Viruses 15 (2023). 98. H. Jia et al., Safety, tolerability, pharmacokinetics, and antiviral activity of the novel core protein allosteric modulator ZM-H1505R (Canocapavir) in chronic hepatitis B patients: a randomized multiple-dose escalation trial. BMC Med 21, 98 (2023). 99. M.-F. Yuen et al., SAT365 - Safety, pharmacokinetics, and antiviral activity of the class II capsid assembly modulator ALG-000184 in subjects with chronic hepatitis B. Journal of Hepatology 77, S835-S836 (2022). 100. K. Fukutomi et al., Capsid Allosteric Modulators Enhance the Innate Immune Response in Hepatitis B Virus-Infected Hepatocytes During Interferon Administration. Hepatol Commun 6, 281-296 (2022). 101. L.-R. Huang, H.-L. Wu, P.-J. Chen, D.-S. Chen, An immunocompetent mouse model for the tolerance of human chronic hepatitis B virus infection. Proceedings of the National Academy of Sciences 103, 17862-17867 (2006). 102. F. Galibert, E. Mandart, F. Fitoussi, P. Tiollais, P. Charnay, Nucleotide sequence of the hepatitis B virus genome (subtype ayw) cloned in E. coli. Nature 281, 646-650 (1979). 103. M. Cemazar, I. Hreljac, G. Sersa, M. Filipic (2010) Construction of EGFP Expressing HepG2 Cell Line Using Electroporation. (Springer Berlin Heidelberg, Berlin, Heidelberg), pp 128-131. 104. A. Kumar, J. Zhang, F. S. Yu, Toll-like receptor 3 agonist poly(I:C)-induced antiviral response in human corneal epithelial cells. Immunology 117, 11-21 (2006). 105. L. C. Platanias, Mechanisms of type-I- and type-II-interferon-mediated signalling. Nature Reviews Immunology 5, 375-386 (2005). 106. S. Vendeville, P. J.-M. B. Raboisson, Y. Debing (2023) Bicyclic and tricyclic compounds. (Google Patents). 107. S. Vendeville, D. B. Smith, L. Beigelman, V. Serebryany (2023) Pyrrole compounds. (Google Patents). 108. N. Mani et al., Preclinical Profile of AB-423, an Inhibitor of Hepatitis B Virus Pregenomic RNA Encapsidation. Antimicrob Agents Chemother 62 (2018). 109. S. Wu et al., Discovery and Mechanistic Study of Benzamide Derivatives That Modulate Hepatitis B Virus Capsid Assembly. Journal of Virology 91, 10.1128/jvi.00519-00517 (2017). 110. K. Fukutomi et al., Capsid Allosteric Modulators Enhance the Innate Immune Response in Hepatitis B Virus–Infected Hepatocytes During Interferon Administration. Hepatology Communications 6, 281-296 (2022). 111. A. D. Huber et al., The Heteroaryldihydropyrimidine Bay 38-7690 Induces Hepatitis B Virus Core Protein Aggregates Associated with Promyelocytic Leukemia Nuclear Bodies in Infected Cells. mSphere 3, 10.1128/mspheredirect.00131-00118 (2018). 112. L. Yang et al., Effect of a hepatitis B virus inhibitor, NZ-4, on capsid formation. Antiviral Research 125, 25-33 (2016). 113. K. Miyakawa et al., Galectin-9 restricts hepatitis B virus replication via p62/SQSTM1-mediated selective autophagy of viral core proteins. Nat Commun 13, 531 (2022). | - |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/99964 | - |
| dc.description.abstract | B型肝炎病毒（Hepatitis B virus, HBV）是一種可引發B型肝炎的DNA病毒，其核心蛋白（HBV-core protein, HBc protein）在合成後會自我組裝形成HBV capsid，並在此過程中包裹病毒的前基因體RNA（pregenomic RNA, pgRNA）。在capsid內，pgRNA經反轉錄作用轉化為鬆弛環狀DNA（relaxed-circular DNA, rcDNA）。成熟的capsid可被包裹形成完整的HBV病毒顆粒，亦可輸送至細胞核以促進病毒的基因轉錄。因此，HBc protein與capsid在HBV的複製中扮演關鍵角色。先前研究顯示，第一型干擾素（Type I interferons）可能透過抑制包裹病毒RNA的HBV capsid形成，或可能導致HBV capsid的降解，進而降低感染細胞中具有複製能力的nucleocapsid數量。而近二十年來，針對HBV capsid的小分子化合物- capsid allosteric modulators（CpAMs）的研究逐年增加。這類化合物可藉由干擾capsid組裝來降低pgRNA的包裹以達到抑制HBV複製的目的。根據其對HBV capsid與HBc protein的影響機制，CpAMs可以粗略地分為兩大類：capsid disruptors與capsid enhancers。其中，capsid disruptors會導致HBc protein錯誤組裝，形成結構異常的HBc polymer；而capsid enhancers則促進不含pgRNA之empty capsid形成。而由於CpAMs與type I interferons皆可影響HBV capsid，但其作用機制各不相同，因此本研究將首先利用HepG2細胞的轉染模型（transfection model）探討不同CpAMs對細胞內HBV capsid之影響，進而評估其是否影響HBc protein相關的type I interferon反應。並希望可以藉由CpAMs來探討type I interferon對於HBV core protein影響的機制。 | zh_TW |
| dc.description.abstract | Hepatitis B virus (HBV) is a DNA virus whose core protein (HBc) self-assembles into a capsid, encapsidating pregenomic RNA (pgRNA) for reverse transcription into relaxed-circular DNA (rcDNA). The mature capsid can either be enveloped to form infectious virions or transported to the nucleus to support viral transcription. Thus, HBc protein and capsid formation are essential for HBV replication. Type I interferons have been shown to inhibit HBV replication, potentially by blocking pgRNA encapsidation or promoting capsid degradation, thereby reducing nucleocapsid levels in infected cells. In recent years, capsid allosteric modulators (CpAMs), small molecules that disrupt normal capsid assembly, have emerged as promising antiviral agents. Depending on their mode of action, CpAMs are broadly categorized into capsid disruptors, which lead to misassembled HBc polymers, and capsid enhancers, which promote the formation of empty capsids lacking pgRNA. Since CpAMs and type I interferons both affect capsid dynamics through different mechanisms, this study uses a HepG2 transfection model to examine the effects of distinct CpAMs on intracellular HBV capsid formation and evaluate their impact on type I interferon responses associated with HBc protein. Furthermore, CpAMs are used as mechanistic probes to elucidate how type I interferons influence HBV core protein. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2025-09-22T16:09:54Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2025-09-22T16:09:54Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 謝辭 i
摘要 ii ABSTRACT iii CONTENTS iv LIST OF FIGURES vii LIST OF TABLES vii CHAPTER 1: Introduction 1 1.1. Hepatitis B virus (HBV) 1 1.1.1. Epidemiology of chronic HBV infection 1 1.1.2. HBV structure and genome 1 1.1.3. Life cycle of HBV 2 1.1.4. HBcAg and HBV capsids 3 1.1.5. New vision of HBV core protein and HBV capsid 4 1.2. Treatment for chronic hepatitis B (CHB) 5 1.2.1. Nucleoside or nucleotide analogues 5 1.2.2. Interferon-α 6 1.3. The anti-HBV agents interfere with HBcAg and capsid expression 7 1.3.1. Type I interferons 7 1.3.1.1. Type I interferons prevented the formation of RNA-containing HBV capsid 7 1.3.1.2. Type I interferons induced the degradation of HBV capsid 8 1.3.2. Capsid allosteric modulators (CpAMs) 9 1.3.2.1. Discovery of CpAMs 9 1.3.2.2. Anti-HBV mechanism and characteristics of CpAMs 10 1.3.2.3. Capsid disruptors 12 1.3.2.4. Capsid enhancers 14 1.3.2.5. Current clinical development of CpAMs 16 1.3.3. The combination treatments of type I interferons and CpAMs 18 1.4. Hypothesis 20 CHAPTER 2: Material and methods 21 2.1. Cell culture 21 2.2. Plasmids 21 2.3. Plasmid purification 22 2.4. Transfection 23 2.5. Compounds and treatment 24 2.5.1. Polyinosinic:polycytidylic acid (poly(I:C)) 24 2.5.2. Capsid allosteric modulators (CpAMs) 24 2.6. Total cell lysis and nuclear and cytoplasmic (N/C) fractionation 24 2.7. Sucrose cushion 26 2.8. Protein analysis 26 2.8.1. Protein quantification by BCA assay 26 2.8.2. Protein sample preparation 27 2.8.3. Western blotting 27 2.9. Probe synthesis 28 2.10. Analysis of intracellular HBV capsids 28 2.10.1. Preparation of samples and native agarose gel electrophoresis (NAGE) 28 2.10.2. Immunoblot of intracellular HBV core particles 29 2.10.3. Probe hybridization of capsid-associated HBV DNA 29 CHAPTER 3: Results 31 3.1. Optimization of transient transfection conditions for HBV DNA expression in HepG2 cells 31 3.2. Treatment of poly(I:C) decreased the amount of cytosolic HBV core protein and HBV capsid, capsid-associated HBV DNA 33 3.3. GLS4 and ABI-H0731 decreased the amounts of cytoplasmic DNA-containing HBV nucleocapsids with distinct effects on HBcAg expression 35 3.4. Combined treatment with CpAMs and poly(I:C) differentially affects HBcAg and capsid expression 36 3.5. The treatments of novel CpAMs showed varied phenotypes in HBc protein and nucleocapsids expression 38 CHAPTER 4: Conclusion and discussion 42 Figure 1. The lifecycle of HBV 51 Figure 2. Transfection with pCMV-HBV resulted in more stable expression of intracellular HBcAg, HBV capsids, and capsid-associated HBV DNA in HepG2 cells compared to pAAV-HBV1.2A 54 Figure 3. Poly(I:C) transfection depleted the cytoplasmic HBcAg and HBV capsids from pCMV-HBV transfected HepG2 cells 57 Figure 4. GLS4 treatments downregulated cytoplasmic HBcAg 60 Figure 5. Treatment with ABI-H0731 resulted in a slight increase in cytoplasmic HBcAg levels 62 Figure 6. Treatments of GLS4 and ABI-H0731 exhibited distinct phenotypes on HBV capsids expressio but both eliminated the amounts of intracellular nucleocapsids 63 Figure 7. Effects of poly(I:C) and CpAMs co-treatment on HBcAg levels 64 Figure 8. Impacts of poly(I:C) and CpAM co-treatment on HBV capsids and encapsidated DNA 65 Figure 9. Treatment with novel CpAMs exhibited differential effects on cytoplasmic HBcAg levels 67 Figure 10. Novel CpAM treatments demonstrated varying impacts on the expression levels of HBV capsid 68 Table 1. Antibodies 69 | - |
| dc.language.iso | en | - |
| dc.subject | B型肝炎病毒（HBV） | zh_TW |
| dc.subject | HBV核心蛋白 | zh_TW |
| dc.subject | HBV capsid | zh_TW |
| dc.subject | 第一型干擾素 | zh_TW |
| dc.subject | capsid allosteric modulators (CpAMs) | zh_TW |
| dc.subject | HepG2細胞 | zh_TW |
| dc.subject | 細胞轉染 | zh_TW |
| dc.subject | HBV-core protein | en |
| dc.subject | cell-based transfection | en |
| dc.subject | HepG2 cells | en |
| dc.subject | capsid allosteric modulators (CpAMs) | en |
| dc.subject | Type I interferons (IFNs) | en |
| dc.subject | HBV capsid | en |
| dc.subject | Hepatitis B virus (HBV) | en |
| dc.title | Capsid allosteric modulators（CpAMs）對B型肝炎病毒之核心蛋白相關第一型干擾素反應的影響 | zh_TW |
| dc.title | Capsid allosteric modulators (CpAMs) on HBV-core protein related type I interferon responses | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 113-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 葉秀慧;黃麗蓉 | zh_TW |
| dc.contributor.oralexamcommittee | Shiou-Hwei Yeh;Li-Rung Huang | en |
| dc.subject.keyword | B型肝炎病毒（HBV）,HBV核心蛋白,HBV capsid,第一型干擾素,capsid allosteric modulators (CpAMs),HepG2細胞,細胞轉染, | zh_TW |
| dc.subject.keyword | Hepatitis B virus (HBV),HBV-core protein,HBV capsid,Type I interferons (IFNs),capsid allosteric modulators (CpAMs),HepG2 cells,cell-based transfection, | en |
| dc.relation.page | 78 | - |
| dc.identifier.doi | 10.6342/NTU202502333 | - |
| dc.rights.note | 同意授權(限校園內公開) | - |
| dc.date.accepted | 2025-07-29 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 微生物學研究所 | - |
| dc.date.embargo-lift | 2027-08-01 | - |
| 顯示於系所單位： | 微生物學科所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-113-2.pdf 未授權公開取用 | 2.71 MB | Adobe PDF | 檢視/開啟 |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。