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研究生:陳牧澤
研究生(外文):Chen, Muh-Tzer
論文名稱:廣效抗病毒活性的抗結核藥物氯法齊明的機理研究
論文名稱(外文):Mechanistic Study of an Anti-tuberculous Drug Clofazimine That Displays broad-spectrum Antiviral Activity
指導教授:龔思豪
指導教授(外文):Kung, Szu-Hao
口試日期:2023-06-28
學位類別:碩士
校院名稱:國立陽明交通大學
系所名稱:醫學生物技術暨檢驗學系
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2023
畢業學年度:111
語文別:中文
論文頁數:75
中文關鍵詞:腸病毒71型氯法齊明病毒進入細胞步驟廣效型抗病毒藥物晚期內體及溶酶體鹼化
外文關鍵詞:EV71clofazimineVirus entrybroad-spectrum antiviral drugsEndolysosomal pH neutralization
相關次數:
  • 被引用被引用:0
  • 點閱點閱:34
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摘要 i
Abstract ii
目錄 iii
圖目錄 v
第一章 緒論 1
第一節 腸病毒概論 1
第二節 親脂性抗分枝桿菌藥物 6
第三節 陽離子兩性親和藥物(CAD) 10
第四節 研究動機與方向 11
第二章 材料與方法 12
第一節 實驗材料 12
壹、細胞株與病毒 (Cell line and Virus) 12
貳、試劑、藥品與溶液 (Reagent, Drugs and Solution) 13
參、抗體 (Antibodies) 17
肆、引子 (primers) 18
伍、質體(plasmid) 18
第二節 實驗方法 18
一、細胞株的培養與操作 18
二、病毒的增殖與定量 20
三、細胞存活率試驗 (MTS assay) 21
四、酸性胞器螢光染色實驗 21
五、病毒加酸逆轉藥物抑制實驗(acid-bypass assay) 22
六、西方墨點法 (Western blot) 23
七、免疫螢光染色 ( IFA) 25
八、藥物添加時間測試抗病毒效果實驗 (Time-of-addition assay) 26
九、病毒結合試驗(binding assay) 27
十、即時定量聚合酶連鎖反應 (Real-time PCR, qPCR) 27
十一、脫殼試驗(uncoating assay) 29
十二、藥物抑制其他血清型之腸病毒與其他種類病毒 30
十三、藥物抑制病毒複製子(replicon)測試 31
第三章 實驗結果 33
第一節 使用CFZ能抑制腸病毒71型感染 33
第二節 確定CFZ抑制在腸病毒71型的哪一階段 34
第三節 CFZ抑制腸病毒71型進入細胞(entry)階段的驗證 37
第四節 CFZ可以抑制其他血清型的腸病毒以及其他種類病毒的複製 39
第四章 討論 40
第五章 圖表 43
第六節 參考資料 53
第七章 附錄 58
附錄一、腸病毒屬之分類[1] 58
附錄二、腸病毒71型質體(pSVA-EV71-GFP) 59
1. van der Linden, L., K.C. Wolthers, and F.J. van Kuppeveld, Replication and Inhibitors of Enteroviruses and Parechoviruses. Viruses, 2015. 7(8): p. 4529-62.
2. Rotbart, H.A., Treatment of picornavirus infections. Antiviral Res, 2002. 53(2): p. 83-98.
3. Yuan, J., et al., Enterovirus A71 Proteins: Structure and Function. Frontiers in Microbiology, 2018. 9.
4. Van Tu, P., et al., Epidemiologic and virologic investigation of hand, foot, and mouth disease, southern Vietnam, 2005. Emerg Infect Dis, 2007. 13(11): p. 1733-41.
5. Thompson, S.R. and P. Sarnow, Enterovirus 71 contains a type I IRES element that functions when eukaryotic initiation factor eIF4G is cleaved. Virology, 2003. 315(1): p. 259-66.
6. Zhu, M., et al., Both ERK1 and ERK2 are required for enterovirus 71 (EV71) efficient replication. Viruses, 2015. 7(3): p. 1344-56.
7. Lin, J.-Y., et al., Viral and host proteins involved in picornavirus life cycle. Journal of Biomedical Science, 2009. 16(1): p. 103.
8. Yang, C.-H., et al., Enterovirus type 71 2A protease functions as a transcriptional activator in yeast. Journal of Biomedical Science, 2010. 17(1): p. 65.
9. Xie, S., et al., DIDS blocks a chloride-dependent current that is mediated by the 2B protein of enterovirus 71. Cell Res, 2011. 21(8): p. 1271-5.
10. Cong, H., et al., Enterovirus 71 2B Induces Cell Apoptosis by Directly Inducing the Conformational Activation of the Proapoptotic Protein Bax. J Virol, 2016. 90(21): p. 9862-9877.
11. Tang, W.F., et al., Reticulon 3 binds the 2C protein of enterovirus 71 and is required for viral replication. J Biol Chem, 2007. 282(8): p. 5888-98.
12. Xiao, X., et al., Enterovirus 3A Facilitates Viral Replication by Promoting Phosphatidylinositol 4-Kinase IIIβ-ACBD3 Interaction. J Virol, 2017. 91(19).
13. Chen, C., et al., Crystal structure of enterovirus 71 RNA-dependent RNA polymerase complexed with its protein primer VPg: implication for a trans mechanism of VPg uridylylation. J Virol, 2013. 87(10): p. 5755-68.
14. Shih, S.R., et al., Mutations at KFRDI and VGK domains of enterovirus 71 3C protease affect its RNA binding and proteolytic activities. J Biomed Sci, 2004. 11(2): p. 239-48.
15. Lei, X., et al., Enterovirus 71 3C inhibits cytokine expression through cleavage of the TAK1/TAB1/TAB2/TAB3 complex. J Virol, 2014. 88(17): p. 9830-41.
16. Li, J., et al., Enterovirus 71 3C Promotes Apoptosis through Cleavage of PinX1, a Telomere Binding Protein. J Virol, 2017. 91(2).
17. Sun, Y., et al., Enterovirus 71 VPg uridylation uses a two-molecular mechanism of 3D polymerase. J Virol, 2012. 86(24): p. 13662-71.
18. Kok, C.C., et al., Modification of the untranslated regions of human enterovirus 71 impairs growth in a cell-specific manner. J Virol, 2012. 86(1): p. 542-52.
19. Lin, J.-Y. and S.-R. Shih, Cell and tissue tropism of enterovirus 71 and other enteroviruses infections. Journal of Biomedical Science, 2014. 21(1): p. 18.
20. Yamayoshi, S., et al., Scavenger receptor B2 is a cellular receptor for enterovirus 71. Nat Med, 2009. 15(7): p. 798-801.
21. Yang, S.L., et al., Annexin II binds to capsid protein VP1 of enterovirus 71 and enhances viral infectivity. J Virol, 2011. 85(22): p. 11809-20.
22. Nishimura, Y., et al., Human P-selectin glycoprotein ligand-1 is a functional receptor for enterovirus 71. Nat Med, 2009. 15(7): p. 794-7.
23. Kobayashi, K. and S. Koike, Cellular receptors for enterovirus A71. Journal of Biomedical Science, 2020. 27(1): p. 23.
24. Hussain, K.M., et al., The essential role of clathrin-mediated endocytosis in the infectious entry of human enterovirus 71. J Biol Chem, 2011. 286(1): p. 309-21.
25. Lin, Y.-W., et al., Human SCARB2-Mediated Entry and Endocytosis of EV71. PLOS ONE, 2012. 7(1): p. e30507.
26. Lin, H.Y., et al., Caveolar endocytosis is required for human PSGL-1-mediated enterovirus 71 infection. J Virol, 2013. 87(16): p. 9064-76.
27. Zhu, Y.Z., et al., The role of lipid rafts in the early stage of Enterovirus 71 infection. Cell Physiol Biochem, 2015. 35(4): p. 1347-59.
28. Baggen, J., et al., The life cycle of non-polio enteroviruses and how to target it. Nature Reviews Microbiology, 2018. 16(6): p. 368-381.
29. Pathak, H.B., et al., Picornavirus genome replication: roles of precursor proteins and rate-limiting steps in oriI-dependent VPg uridylylation. J Biol Chem, 2008. 283(45): p. 30677-88.
30. Shingler, K.L., et al., The Enterovirus 71 A-particle Forms a Gateway to Allow Genome Release: A CryoEM Study of Picornavirus Uncoating. PLOS Pathogens, 2013. 9(3): p. e1003240.
31. Chen, L.C., et al., Enterovirus 71 infection induces Fas ligand expression and apoptosis of Jurkat cells. J Med Virol, 2006. 78(6): p. 780-6.
32. Solomon, T., et al., Virology, epidemiology, pathogenesis, and control of enterovirus 71. Lancet Infect Dis, 2010. 10(11): p. 778-90.
33. Rhoades, R.E., et al., Enterovirus infections of the central nervous system. Virology, 2011. 411(2): p. 288-305.
34. Liu, S.L., et al., Comparative epidemiology and virology of fatal and nonfatal cases of hand, foot and mouth disease in mainland China from 2008 to 2014. Rev Med Virol, 2015. 25(2): p. 115-28.
35. Bauer, L., et al., Direct-acting antivirals and host-targeting strategies to combat enterovirus infections. Curr Opin Virol, 2017. 24: p. 1-8.
36. Li, M.L., et al., Enterovirus A71 Vaccines. Vaccines (Basel), 2021. 9(3).
37. Nguyen, T.T., et al., Efficacy, safety, and immunogenicity of an inactivated, adjuvanted enterovirus 71 vaccine in infants and children: a multiregion, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet, 2022. 399(10336): p. 1708-1717.
38. Barry, V.C., The thyroid and tuberculosis. Nature, 1946. 158(4004): p. 131.
39. Barry, V.C., et al., A New Series of Phenazines (Rimino-Compounds) With High Antituberculosis Activity. Nature, 1957. 179(4568): p. 1013-1015.
40. Barry, V.C. and M.L. Conalty, THE ANTIMYCOBACTERIAL ACTIVITY OF B 663. Lepr Rev, 1965. 36: p. 3-7.
41. Cholo, M.C., et al., Clofazimine: current status and future prospects. J Antimicrob Chemother, 2012. 67(2): p. 290-8.
42. .
43. .
44. Yawalkar, S.J. and W. Vischer, Lamprene (clofazimine) in leprosy. Basic information. Lepr Rev, 1979. 50(2): p. 135-44.
45. Vischer, W.A., The experimental properties of G 30 320 (B 663)--a new anti-leprotic agent. Lepr Rev, 1969. 40(2): p. 107-10.
46. Van Deun, A., et al., Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med, 2010. 182(5): p. 684-92.
47. .
48. Reddy, V.M., J.F. O'Sullivan, and P.R. Gangadharam, Antimycobacterial activities of riminophenazines. J Antimicrob Chemother, 1999. 43(5): p. 615-23.
49. O'Connor, R., J.F. O'Sullivan, and R. O'Kennedy, The pharmacology, metabolism, and chemistry of clofazimine. Drug Metab Rev, 1995. 27(4): p. 591-614.
50. Barry, V.C., et al., Absorption, distribution and retention of the riminocompounds in the experimental animal. Ir J Med Sci, 1960. 416: p. 345-52.
51. Baijnath, S., et al., Clofazimine protects against Mycobacterium tuberculosis dissemination in the central nervous system following aerosol challenge in a murine model. Int J Antimicrob Agents, 2018. 51(1): p. 77-81.
52. Baik, J. and G.R. Rosania, Molecular imaging of intracellular drug-membrane aggregate formation. Mol Pharm, 2011. 8(5): p. 1742-9.
53. Baik, J., et al., Multiscale distribution and bioaccumulation analysis of clofazimine reveals a massive immune system-mediated xenobiotic sequestration response. Antimicrob Agents Chemother, 2013. 57(3): p. 1218-30.
54. Prideaux, B., et al., The association between sterilizing activity and drug distribution into tuberculosis lesions. Nat Med, 2015. 21(10): p. 1223-7.
55. Strydom, N., et al., Tuberculosis drugs' distribution and emergence of resistance in patient's lung lesions: A mechanistic model and tool for regimen and dose optimization. PLoS Med, 2019. 16(4): p. e1002773.
56. Cholo, M.C., et al., Mechanisms of action and therapeutic efficacies of the lipophilic antimycobacterial agents clofazimine and bedaquiline. J Antimicrob Chemother, 2017. 72(2): p. 338-353.
57. Wu, J., et al., Clofazimine: A Promising Inhibitor of Rabies Virus. Frontiers in Pharmacology, 2021. 12.
58. Faouzi, M., J. Starkus, and R. Penner, State-dependent blocking mechanism of Kv 1.3 channels by the antimycobacterial drug clofazimine. British journal of pharmacology, 2015. 172(21): p. 5161-5173.
59. Gaudin, Y., et al., Low-pH conformational changes of rabies virus glycoprotein and their role in membrane fusion. J Virol, 1993. 67(3): p. 1365-72.
60. Yuan, S., et al., Clofazimine broadly inhibits coronaviruses including SARS-CoV-2. Nature, 2021. 593(7859): p. 418-423.
61. Kreutzberger, A.J.B., et al., SARS-CoV-2 requires acidic pH to infect cells. Proceedings of the National Academy of Sciences, 2022. 119(38): p. e2209514119.
62. Salata, C., et al., Antiviral activity of cationic amphiphilic drugs. Expert Rev Anti Infect Ther, 2017. 15(5): p. 483-492.
63. Woldemichael, T., et al., Reverse Engineering the Intracellular Self-Assembly of a Functional Mechanopharmaceutical Device. Scientific Reports, 2018. 8(1): p. 2934.
64. Tang, Q., et al., Emetine protects mice from enterovirus infection by inhibiting viral translation. Antiviral Research, 2020. 173: p. 104650.
65. Chua, J., et al., pH Alkalinization by Chloroquine Suppresses Pathogenic Burkholderia Type 6 Secretion System 1 and Multinucleated Giant Cells. Infect Immun, 2017. 85(1).
66. Weed Darin, J., et al., Acidic pH Mediates Changes in Antigenic and Oligomeric Conformation of Herpes Simplex Virus gB and Is a Determinant of Cell-Specific Entry. Journal of Virology, 2018. 92(17): p. 10.1128/jvi.01034-18.
67. Matlin, K.S., et al., Infectious entry pathway of influenza virus in a canine kidney cell line. J Cell Biol, 1981. 91(3 Pt 1): p. 601-13.
68. Muralidar, S., G. Gopal, and S. Visaga Ambi, Targeting the viral-entry facilitators of SARS-CoV-2 as a therapeutic strategy in COVID-19. J Med Virol, 2021. 93(9): p. 5260-5276.
69. Wunner, W.H. and K.-K. Conzelmann, Chapter 2 - Rabies Virus, in Rabies (Third Edition), A.C. Jackson, Editor. 2013, Academic Press: Boston. p. 17-60.
70. Salem, II, G. Steffan, and N. Duzgunes, Efficacy of clofazimine-modified cyclodextrin against Mycobacterium avium complex in human macrophages. Int J Pharm, 2003. 260(1): p. 105-14.
71. Narang, A.S. and A.K. Srivastava, Evaluation of Solid Dispersions of Clofazimine. Drug Development and Industrial Pharmacy, 2002. 28(8): p. 1001-1013.
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