跳到主要內容

臺灣博碩士論文加值系統

(44.192.247.184) 您好!臺灣時間:2023/02/06 10:54
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

: 
twitterline
研究生:侯心宇
研究生(外文):Hsin-Yu Hou
論文名稱:蒽環黴素類化合物抑制腸病毒71型複製的作用機制
論文名稱(外文):Action mechanisms of Anthracyclines as inhibitors of Enterovirus 71 replication
指導教授:龔思豪
指導教授(外文):Szu-Hao Kung
學位類別:碩士
校院名稱:國立陽明大學
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:2014
畢業學年度:102
語文別:中文
論文頁數:83
相關次數:
  • 被引用被引用:0
  • 點閱點閱:184
  • 評分評分:
  • 下載下載:1
  • 收藏至我的研究室書目清單書目收藏:0
腸病毒71型的感染常會引起嬰幼兒神經方面的併發症,甚至造成死亡。然而,目前並無發展出可供臨床上所使用的抗腸病毒藥物。利用實驗室篩選平台篩選出的Idarubicin (IDR),其屬於蒽環黴素類(anthracycline)的化合物,實驗中發現只需要μM的藥物濃度,就具有顯著抑制EV71的效果。IDR不但能減緩EV71感染後細胞病變的產生,亦能降低細胞死亡率。並且,IDR對於其他型別的腸病毒也有不錯的抑制效果,且細胞毒性小,抑制機制方面也與topoisomerase II inhibitor 的功能無關。

此外,兩個IDR的結構類似物,Daunorubicin (DNR)及Epirubicin (EPI)同樣具有抑制EV71的能力,證明很有可能是這類藥物的某種核心結構,造成病毒的抑制。經由在病毒複製週期的不同時間點加藥之實驗結果中,看到IDR主要作用在EV71感染後的0 ~ 5小時。為了深入探討藥物的作用機制,得知EV71在病毒蛋白合成時已受到IDR的抑制;並且透過雙冷光報導基因的偵測,這類藥物還會選擇性抑制病毒核醣體進入區的轉譯起始;不過細胞內p53 mRNA上的IRES結構,卻不受到IDR的抑制。另外,從競爭型透析試驗中發現,IDR能夠嵌入病毒核醣體進入區,抑制此區的轉譯起始,並與IDR結合上IRES RNA的能力呈現正相關。由於IDR已經是FDA通過的臨床用藥,因此本篇的實驗結果可提供IDR及其結構類似物一新的治療方式及策略以控制腸病毒71型的感染。

Enterovirus 71 (EV71) causes life-threatening diseases with neurological manifestations in young children. However, the treatment of EV71 infections remains a significantly unmet medical need. A drug screening identified IDRrubicin (IDR), an anthracycline compound, which showed anti-EV71 activities in the sub-μM range. IDR significantly protected infected cells from the cytopathic effects and cell death caused by EV71 infections. The antiviral effects can be extended to several other enterovirus species, and the effects were independent of cytotoxicity or topoisomerase inhibition. Two structural analogues, daunorubicin and epirubicin, also displayed anti-enterovirus effects, stressing the important of the core structure of this class of compounds. A time-of-addition study revealed that IDR strongly inhibited EV71 infections at 0-5 h post-infection. To unfold the mechanism of action, the anthracycline compounds were demonstrated to effectively intervene with viral protein synthesis. Moreover, these compounds were shown to suppress the virus internal ribosomal entry site (IRES)-mediated translation initiation by using a bicistronic reporter assay; conversely, IRESs present in the cellular p53 transcript were not sensitive to IDR. Competition analysis demonstrated that the degree of inhibition of IRES-mediated translation by IDR correlated well with the affinity of binding between IDR and the corresponding IRESs. This new use of anthracycline compounds as selective enteroviral IRES intercalating agents may provide new perspectives for therapeutic strategies for controlling EV71 infections and their consequences.
目錄
目錄 i
中文摘要 iv
Abstract v
第一章 緒論 1
第一節 腸病毒71型 1
一、分類及特性 1
二、基因體及蛋白質 2
三、複製週期 3
四、流行病學 4
五、抗病毒藥物發展 4
第二節 抗EV71藥物的篩選 7
一、螢光共振能量轉移 7
二、穩定表現螢光共振能量轉移之細胞株 7
第三節 病毒內部核醣體進入區 9
一、腸病毒IRES結構 9
二、IRES trans-acting factors (ITAFs) 10
第四節 研究動機與方向 12
第二章 實驗材料與方法 13
第一節 實驗材料 13
一、細胞與病毒 (Cell lines and Virus) 13
二、藥品 (Drugs) 13
三、試劑套組與酵素 (Kit and Enzyme) 15
四、寡核苷酸和引子 (Oligonucleotide and Primer) 16
五、質體 (Plasmids) 17
六、抗體和染劑 (Antibodies and Dye) 17
七、溶液 (Solution) 18
第二節 實驗方法 22
一、細胞株培養 22
二、病毒培養與定量 23
三、質體建構 25
四、病毒造成的細胞病變觀察 30
五、細胞存活率試驗 (MTT assay) 30
六、免疫螢光染色 (IFA) 30
七、西方墨點法 (Western blot) 31
八、RNA製備 34
九、RNA轉染 35
十、雙冷光報導基因偵測 (Dual luciferase reporter assay) 36
十一、IRES RNA製備 36
十二、競爭型透析試驗 (Competition dialysis assay) 37
十三、EV71對IDR的抗藥性測試 38
第三章 實驗結果 39
第一節 Anthracyclines對於腸病毒71型的抑制能力 39
一、藥物抑制效果與劑量 39
二、藥物濃度的細胞毒性 40
三、選擇性指數評估 41
第二節 Anthracyclines的藥物作用機制探討 41
一、藥物作用時間點確認 41
二、藥物作用機制與Topoisomerase II inhibitor的並無關係 41
三、Anthracyclines藥物能夠抑制EV71蛋白質的產生 42
四、Anthracyclines藥物可選擇性EV71 IRES,而不影響細胞p53 IRES 42
五、Anthracyclines藥物亦能抑制其他腸病毒之IRES 43
六、IDR對腸病毒IRES有較強的親和力 44
七、EV71並不會對IDR產生抗藥性 45
第四章 討論 46
第五章 圖表 50
圖一 Anthracyclines藥物能夠抑制EV71造成的細胞病變及細胞死亡 50
圖二 Anthracyclines藥物對於EV71感染細胞比例的影響 51
圖三 Anthracyclines藥物的細胞毒性及CC50 52
圖四 IDR對於EV71複製早期才有抑制作用 53
圖五 非anthracyclines的Topoisomerase II抑制劑無抑制EV71的作用 54
圖六 Anthracyclines藥物對病毒蛋白表現的抑制 55
圖七 各種dual luciferase-RNA結構示意圖 56
圖八 Anthracyclines藥物會選擇性抑制EV71 IRES,而不影響細胞性IRES 57
圖九 Anthracyclines藥物對於Echovirus 9及Coxsackievirus A16 IRES的抑制 59
圖十 藥物會選擇性結合到病毒的IRES 60
表一 Anthracyclines藥物對腸病毒的抑制能力 61
第六章 參考文獻 62
第七章 附錄 72
附錄一、微小RNA病毒科分類 72
附錄二、腸病毒的結構 73
附錄三、腸病毒基因體組成 73
附錄四、腸病毒的複製週期 74
附錄五、EV71在人類橫紋肌肉瘤細胞中的複製階段 74
附錄六、各種抗腸病毒71型的藥物結構 75
附錄七、各種抗腸病毒71型的藥物機制 76
附錄八、HeLa-G2AwtR細胞的篩選原理之概念圖 77
附錄九、GFP2與DsRed2激發及放射光譜 77
附錄十、以HeLa-G2AwtR細胞篩選抗EV71藥物的結果 78
附錄十一、不同類別的IRES 79
附錄十二、腸病毒71型的IRES結構 79
附錄十三、競爭型透析試驗示意圖 80
附錄十四、Anthracyclines與非anthracyclines之藥物結構 81
附錄十五、pCREL-dual luciferase-T7- EV71 IRES質體 82
附錄十六、EV71經IDR持續處理後並無抗藥性病毒株產生 83

1. De Jesus, N.H. Epidemics to eradication: the modern history of poliomyelitis. Virol J 4, 70 (2007).
2. Ho, M. et al. An epidemic of enterovirus 71 infection in Taiwan. Taiwan Enterovirus Epidemic Working Group. N Engl J Med 341, 929-35 (1999).
3. Chang, L.Y., Huang, Y.C. & Lin, T.Y. Fulminant neurogenic pulmonary oedema with hand, foot, and mouth disease. Lancet 352, 367-8 (1998).
4. McMinn, P.C. An overview of the evolution of enterovirus 71 and its clinical and public health significance. FEMS Microbiol Rev 26, 91-107 (2002).
5. Rotbart, H.A. Treatment of picornavirus infections. Antiviral Res 53, 83-98 (2002).
6. De Palma, A.M., Vliegen, I., De Clercq, E. & Neyts, J. Selective inhibitors of picornavirus replication. Med Res Rev 28, 823-84 (2008).
7. Bedard, K.M. & Semler, B.L. Regulation of picornavirus gene expression. Microbes Infect 6, 702-13 (2004).
8. Strebel, K. & Beck, E. A second protease of foot-and-mouth disease virus. J Virol 58, 893-9 (1986).
9. Svitkin, Y.V., Gorbalenya, A.E., Kazachkov, Y.A. & Agol, V.I. Encephalomyocarditis virus-specific polypeptide p22 possessing a proteolytic activity: preliminary mapping on the viral genome. FEBS Lett 108, 6-9 (1979).
10. Toyoda, H. et al. A second virus-encoded proteinase involved in proteolytic processing of poliovirus polyprotein. Cell 45, 761-70 (1986).
11. Aldabe, R., Barco, A. & Carrasco, L. Membrane permeabilization by poliovirus proteins 2B and 2BC. J Biol Chem 271, 23134-7 (1996).
12. de Jong, A.S. et al. Determinants for membrane association and permeabilization of the coxsackievirus 2B protein and the identification of the Golgi complex as the target organelle. J Biol Chem 278, 1012-21 (2003).
13. van Kuppeveld, F.J. et al. Coxsackievirus protein 2B modifies endoplasmic reticulum membrane and plasma membrane permeability and facilitates virus release. EMBO J 16, 3519-32 (1997).
14. Choe, S.S., Dodd, D.A. & Kirkegaard, K. Inhibition of cellular protein secretion by picornaviral 3A proteins. Virology 337, 18-29 (2005).
15. Paul, A.V., van Boom, J.H., Filippov, D. & Wimmer, E. Protein-primed RNA synthesis by purified poliovirus RNA polymerase. Nature 393, 280-4 (1998).
16. Svitkin, Y.V. et al. Internal translation initiation on poliovirus RNA: further characterization of La function in poliovirus translation in vitro. J Virol 68, 1544-50 (1994).
17. Thompson, S.R. & Sarnow, P. Enterovirus 71 contains a type I IRES element that functions when eukaryotic initiation factor eIF4G is cleaved. Virology 315, 259-66 (2003).
18. Pelletier, J. & Sonenberg, N. Internal initiation of translation of eukaryotic mRNA directed by a sequence derived from poliovirus RNA. Nature 334, 320-5 (1988).
19. Lu, J. et al. Viral kinetics of enterovirus 71 in human abdomyosarcoma cells. World J Gastroenterol 17, 4135-42 (2011).
20. Schmidt, N.J., Lennette, E.H. & Ho, H.H. An apparently new enterovirus isolated from patients with disease of the central nervous system. J Infect Dis 129, 304-9 (1974).
21. Bible, J.M., Pantelidis, P., Chan, P.K. & Tong, C.Y. Genetic evolution of enterovirus 71: epidemiological and pathological implications. Rev Med Virol 17, 371-9 (2007).
22. Alexander, J.P., Jr., Baden, L., Pallansch, M.A. & Anderson, L.J. Enterovirus 71 infections and neurologic disease--United States, 1977-1991. J Infect Dis 169, 905-8 (1994).
23. Nagy, G., Takatsy, S., Kukan, E., Mihaly, I. & Domok, I. Virological diagnosis of enterovirus type 71 infections: experiences gained during an epidemic of acute CNS diseases in Hungary in 1978. Arch Virol 71, 217-27 (1982).
24. Chumakov, M. et al. Enterovirus 71 isolated from cases of epidemic poliomyelitis-like disease in Bulgaria. Arch Virol 60, 329-40 (1979).
25. Shimizu, H. et al. Enterovirus 71 from fatal and nonfatal cases of hand, foot and mouth disease epidemics in Malaysia, Japan and Taiwan in 1997-1998. Jpn J Infect Dis 52, 12-5 (1999).
26. Ishimaru, Y., Nakano, S., Yamaoka, K. & Takami, S. Outbreaks of hand, foot, and mouth disease by enterovirus 71. High incidence of complication disorders of central nervous system. Arch Dis Child 55, 583-8 (1980).
27. Gilbert, G.L. et al. Outbreak of enterovirus 71 infection in Victoria, Australia, with a high incidence of neurologic involvement. Pediatr Infect Dis J 7, 484-8 (1988).
28. da Silva, E.E., Winkler, M.T. & Pallansch, M.A. Role of enterovirus 71 in acute flaccid paralysis after the eradication of poliovirus in Brazil. Emerg Infect Dis 2, 231-3 (1996).
29. Lum, L.C., Wong, K.T., Lam, S.K., Chua, K.B. & Goh, A.Y. Neurogenic pulmonary oedema and enterovirus 71 encephalomyelitis. Lancet 352, 1391 (1998).
30. Samuda, G.M., Chang, W.K., Yeung, C.Y. & Tang, P.S. Monoplegia caused by Enterovirus 71: an outbreak in Hong Kong. Pediatr Infect Dis J 6, 206-8 (1987).
31. Chen, S.C., Chang, H.L., Yan, T.R., Cheng, Y.T. & Chen, K.T. An eight-year study of epidemiologic features of enterovirus 71 infection in Taiwan. Am J Trop Med Hyg 77, 188-91 (2007).
32. Shimizu, H. et al. Molecular epidemiology of enterovirus 71 infection in the Western Pacific Region. Pediatr Int 46, 231-5 (2004).
33. Lin, T.Y., Twu, S.J., Ho, M.S., Chang, L.Y. & Lee, C.Y. Enterovirus 71 outbreaks, Taiwan: occurrence and recognition. Emerg Infect Dis 9, 291-3 (2003).
34. Lee, P.I., Lee, C.Y. & Wang, T.R. Recommendations for management of severe enterovirus infection in Taiwan. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi 39, 217 (1998).
35. Kuo, R.L. & Shih, S.R. Strategies to develop antivirals against enterovirus 71. Virol J 10, 28 (2013).
36. Nishimura, Y. et al. Human P-selectin glycoprotein ligand-1 is a functional receptor for enterovirus 71. Nat Med 15, 794-7 (2009).
37. Yamayoshi, S. et al. Scavenger receptor B2 is a cellular receptor for enterovirus 71. Nat Med 15, 798-801 (2009).
38. Zhang, G. et al. In vitro and in vivo evaluation of ribavirin and pleconaril antiviral activity against enterovirus 71 infection. Arch Virol 157, 669-79 (2012).
39. Shia, K.S. et al. Design, synthesis, and structure-activity relationship of pyridyl imidazolidinones: a novel class of potent and selective human enterovirus 71 inhibitors. J Med Chem 45, 1644-55 (2002).
40. Senior, K. FDA panel rejects common cold treatment. Lancet Infect Dis 2, 264 (2002).
41. Shih, S.R. et al. Mutation in enterovirus 71 capsid protein VP1 confers resistance to the inhibitory effects of pyridyl imidazolidinone. Antimicrob Agents Chemother 48, 3523-9 (2004).
42. Weng, T.Y. et al. Lactoferrin inhibits enterovirus 71 infection by binding to VP1 protein and host cells. Antiviral Res 67, 31-7 (2005).
43. Yen, M.H., Chiu, C.H., Huang, Y.C. & Lin, T.Y. Effects of lactoferrin-containing formula in the prevention of enterovirus and rotavirus infection and impact on serum cytokine levels: a randomized trial. Chang Gung Med J 34, 395-402 (2011).
44. Matthews, D.A. et al. Structure-assisted design of mechanism-based irreversible inhibitors of human rhinovirus 3C protease with potent antiviral activity against multiple rhinovirus serotypes. Proc Natl Acad Sci U S A 96, 11000-7 (1999).
45. Lee, J.C. et al. A mammalian cell-based reverse two-hybrid system for functional analysis of 3C viral protease of human enterovirus 71. Anal Biochem 375, 115-23 (2008).
46. Lu, G. et al. Enterovirus 71 and coxsackievirus A16 3C proteases: binding to rupintrivir and their substrates and anti-hand, foot, and mouth disease virus drug design. J Virol 85, 10319-31 (2011).
47. Tsai, M.T. et al. Real-time monitoring of human enterovirus (HEV)-infected cells and anti-HEV 3C protease potency by fluorescence resonance energy transfer. Antimicrob Agents Chemother 53, 748-55 (2009).
48. Binford, S.L. et al. Conservation of amino acids in human rhinovirus 3C protease correlates with broad-spectrum antiviral activity of rupintrivir, a novel human rhinovirus 3C protease inhibitor. Antimicrob Agents Chemother 49, 619-26 (2005).
49. Patick, A.K. et al. In vitro antiviral activity of AG7088, a potent inhibitor of human rhinovirus 3C protease. Antimicrob Agents Chemother 43, 2444-50 (1999).
50. Zhang, K.E., Hee, B., Lee, C.A., Liang, B. & Potts, B.C. Liquid chromatography-mass spectrometry and liquid chromatography-NMR characterization of in vitro metabolites of a potent and irreversible peptidomimetic inhibitor of rhinovirus 3C protease. Drug Metab Dispos 29, 729-34 (2001).
51. Patick, A.K. et al. In vitro antiviral activity and single-dose pharmacokinetics in humans of a novel, orally bioavailable inhibitor of human rhinovirus 3C protease. Antimicrob Agents Chemother 49, 2267-75 (2005).
52. Dragovich, P.S. et al. Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 8. Pharmacological optimization of orally bioavailable 2-pyridone-containing peptidomimetics. J Med Chem 46, 4572-85 (2003).
53. Patick, A.K. Rhinovirus chemotherapy. Antiviral Res 71, 391-6 (2006).
54. Cui, S. et al. Crystal structure of human enterovirus 71 3C protease. J Mol Biol 408, 449-61 (2011).
55. Goris, N. et al. 2'-C-methylcytidine as a potent and selective inhibitor of the replication of foot-and-mouth disease virus. Antiviral Res 73, 161-8 (2007).
56. Harki, D.A. et al. Synthesis and antiviral activity of 5-substituted cytidine analogues: identification of a potent inhibitor of viral RNA-dependent RNA polymerases. J Med Chem 49, 6166-9 (2006).
57. Kishimoto, C., Crumpacker, C.S. & Abelmann, W.H. Ribavirin treatment of murine coxsackievirus B3 myocarditis with analyses of lymphocyte subsets. J Am Coll Cardiol 12, 1334-41 (1988).
58. Graci, J.D. et al. Lethal mutagenesis of picornaviruses with N-6-modified purine nucleoside analogues. Antimicrob Agents Chemother 52, 971-9 (2008).
59. Chen, T.C. et al. Novel antiviral agent DTriP-22 targets RNA-dependent RNA polymerase of enterovirus 71. Antimicrob Agents Chemother 53, 2740-7 (2009).
60. Wikel, J.H. et al. Synthesis of syn and anti isomers of 6-[[(hydroxyimino)phenyl]methyl]-1-[(1-methylethyl)sulfonyl]-1H-benzimidazol-2-am ine. Inhibitors of rhinovirus multiplication. J Med Chem 23, 368-72 (1980).
61. Heinz, B.A. & Vance, L.M. The antiviral compound enviroxime targets the 3A coding region of rhinovirus and poliovirus. J Virol 69, 4189-97 (1995).
62. Hope, D.A., Diamond, S.E. & Kirkegaard, K. Genetic dissection of interaction between poliovirus 3D polymerase and viral protein 3AB. J Virol 71, 9490-8 (1997).
63. Giachetti, C., Hwang, S.S. & Semler, B.L. cis-acting lesions targeted to the hydrophobic domain of a poliovirus membrane protein involved in RNA replication. J Virol 66, 6045-57 (1992).
64. Phillpotts, R.J. et al. The activity of enviroxime against rhinovirus infection in man. Lancet 1, 1342-4 (1981).
65. Arita, M., Takebe, Y., Wakita, T. & Shimizu, H. A bifunctional anti-enterovirus compound that inhibits replication and the early stage of enterovirus 71 infection. J Gen Virol 91, 2734-44 (2010).
66. Novina, C.D. et al. siRNA-directed inhibition of HIV-1 infection. Nat Med 8, 681-6 (2002).
67. Jacque, J.M., Triques, K. & Stevenson, M. Modulation of HIV-1 replication by RNA interference. Nature 418, 435-8 (2002).
68. Gitlin, L., Karelsky, S. & Andino, R. Short interfering RNA confers intracellular antiviral immunity in human cells. Nature 418, 430-4 (2002).
69. Kapadia, S.B., Brideau-Andersen, A. & Chisari, F.V. Interference of hepatitis C virus RNA replication by short interfering RNAs. Proc Natl Acad Sci U S A 100, 2014-8 (2003).
70. Yuan, J., Cheung, P.K., Zhang, H.M., Chau, D. & Yang, D. Inhibition of coxsackievirus B3 replication by small interfering RNAs requires perfect sequence match in the central region of the viral positive strand. J Virol 79, 2151-9 (2005).
71. Merl, S. et al. Targeting 2A protease by RNA interference attenuates coxsackieviral cytopathogenicity and promotes survival in highly susceptible mice. Circulation 111, 1583-92 (2005).
72. Tan, E.L., Wong, A.P. & Poh, C.L. Development of potential antiviral strategy against coxsackievirus B4. Virus Res 150, 85-92 (2010).
73. Sim, A.C., Luhur, A., Tan, T.M., Chow, V.T. & Poh, C.L. RNA interference against enterovirus 71 infection. Virology 341, 72-9 (2005).
74. Lu, W.W., Hsu, Y.Y., Yang, J.Y. & Kung, S.H. Selective inhibition of enterovirus 71 replication by short hairpin RNAs. Biochem Biophys Res Commun 325, 494-9 (2004).
75. Tan, E.L., Tan, T.M., Tak Kwong Chow, V. & Poh, C.L. Inhibition of enterovirus 71 in virus-infected mice by RNA interference. Mol Ther 15, 1931-8 (2007).
76. Merl, S. & Wessely, R. Anti-coxsackieviral efficacy of RNA interference is highly dependent on genomic target selection and emergence of escape mutants. Oligonucleotides 17, 44-53 (2007).
77. Liu, M.L. et al. Type I interferons protect mice against enterovirus 71 infection. J Gen Virol 86, 3263-9 (2005).
78. Yi, L., He, Y., Chen, Y., Kung, H.F. & He, M.L. Potent inhibition of human enterovirus 71 replication by type I interferon subtypes. Antivir Ther 16, 51-8 (2011).
79. Lei, X. et al. Cleavage of the adaptor protein TRIF by enterovirus 71 3C inhibits antiviral responses mediated by Toll-like receptor 3. J Virol 85, 8811-8 (2011).
80. Lei, X. et al. The 3C protein of enterovirus 71 inhibits retinoid acid-inducible gene I-mediated interferon regulatory factor 3 activation and type I interferon responses. J Virol 84, 8051-61 (2010).
81. Lei, X. et al. Cleavage of interferon regulatory factor 7 by enterovirus 71 3C suppresses cellular responses. J Virol 87, 1690-8 (2013).
82. Lu, J. et al. Enterovirus 71 disrupts interferon signaling by reducing the level of interferon receptor 1. J Virol 86, 3767-76 (2012).
83. Eidne, K.A., Kroeger, K.M. & Hanyaloglu, A.C. Applications of novel resonance energy transfer techniques to study dynamic hormone receptor interactions in living cells. Trends Endocrinol Metab 13, 415-21 (2002).
84. Jares-Erijman, E.A. & Jovin, T.M. FRET imaging. Nat Biotechnol 21, 1387-95 (2003).
85. Pollok, B.A. & Heim, R. Using GFP in FRET-based applications. Trends Cell Biol 9, 57-60 (1999).
86. Wu, P. & Brand, L. Resonance energy transfer: methods and applications. Anal Biochem 218, 1-13 (1994).
87. Tsien, R.Y., Bacskai, B.J. & Adams, S.R. FRET for studying intracellular signalling. Trends Cell Biol 3, 242-5 (1993).
88. Demchenko, A.P. The concept of lambda-ratiometry in fluorescence sensing and imaging. J Fluoresc 20, 1099-128 (2010).
89. Srikun, D., Miller, E.W., Domaille, D.W. & Chang, C.J. An ICT-based approach to ratiometric fluorescence imaging of hydrogen peroxide produced in living cells. J Am Chem Soc 130, 4596-7 (2008).
90. Hsu, Y.Y., Liu, Y.N., Wang, W., Kao, F.J. & Kung, S.H. In vivo dynamics of enterovirus protease revealed by fluorescence resonance emission transfer (FRET) based on a novel FRET pair. Biochem Biophys Res Commun 353, 939-45 (2007).
91. Niepmann, M. Internal translation initiation of picornaviruses and hepatitis C virus. Biochimica et Biophysica Acta (2009).
92. Jang, S.K. Internal initiation: IRES elements of picornaviruses and hepatitis c virus. Virus Research 119, 2-15 (2006).
93. Martinez-Salas, E., Ramos, R., Lafuente, E. & Lopez de Quinto, S. Functional interactions in internal translation initiation directed by viral and cellular IRES elements. Journal of General Virology 82, 973-84 (2001).
94. Costa-Mattioli, M., Svitkin, Y. & Sonenberg, N. La autoantigen is necessary for optimal function of the poliovirus and hepatitis C virus internal ribosome entry site in vivo and in vitro. Molecular and Cellular Biology 24, 6861-70 (2004).
95. Meerovitch, K. et al. La autoantigen enhances and corrects aberrant translation of poliovirus RNA in reticulocyte lysate. Journal of Virology 67, 3798-807 (1993).
96. Florez, P.M., Sessions, O.M., Wagner, E.J., Gromeier, M. & Garcia-Blanco, M.A. The polypyrimidine tract binding protein is required for efficient picornavirus gene expression and propagation. Journal of Virology 79, 6172-9 (2005).
97. Hunt, S.L. & Jackson, R.J. Polypyrimidine-tract binding protein (PTB) is necessary, but not sufficient, for efficient internal initiation of translation of human rhinovirus-2 RNA. RNA 5, 344-59 (1999).
98. Hellen, C.U. et al. A cytoplasmic 57-kDa protein that is required for translation of picornavirus RNA by internal ribosomal entry is identical to the nuclear pyrimidine tract-binding protein. Proceedings of the National Academy of Sciences of the United States of America 90, 7642-6 (1993).
99. Walter, B.L., Nguyen, J.H., Ehrenfeld, E. & Semler, B.L. Differential utilization of poly(rC) binding protein 2 in translation directed by picornavirus IRES elements. RNA 5, 1570-85 (1999).
100. Blyn, L.B. et al. Poly(rC) binding protein 2 binds to stem-loop IV of the poliovirus RNA 5' noncoding region: identification by automated liquid chromatography-tandem mass spectrometry. Proceedings of the National Academy of Sciences of the United States of America 93, 11115-20 (1996).
101. Boussadia, O. et al. Unr is required in vivo for efficient initiation of translation from the internal ribosome entry sites of both rhinovirus and poliovirus. Journal of Virology 77, 3353-9 (2003).
102. Hunt, S.L., Hsuan, J.J., Totty, N. & Jackson, R.J. unr, a cellular cytoplasmic RNA-binding protein with five cold-shock domains, is required for internal initiation of translation of human rhinovirus RNA. Genes and Development 13, 437-48 (1999).
103. Kaminski, A. & Jackson, R.J. The polypyrimidine tract binding protein (PTB) requirement for internal initiation of translation of cardiovirus RNAs is conditional rather than absolute. RNA 4, 626-38 (1998).
104. Niepmann, M., Petersen, A., Meyer, K. & Beck, E. Functional involvement of polypyrimidine tract-binding protein in translation initiation complexes with the internal ribosome entry site of foot-and-mouth disease virus. Journal of Virology 71, 8330-9 (1997).
105. Ali, N. & Siddiqui, A. Interaction of polypyrimidine tract-binding protein with the 5' noncoding region of the hepatitis C virus RNA genome and its functional requirement in internal initiation of translation. Journal of Virology 69, 6367-75 (1995).
106. Walter, B.L., Parsley, T.B., Ehrenfeld, E. & Semler, B.L. Distinct poly(rC) binding protein KH domain determinants for poliovirus translation initiation and viral RNA replication. Journal of Virology 76, 12008-22 (2002).
107. Gamarnik, A.V. & Andino, R. Interactions of viral protein 3CD and poly(rC) binding protein with the 5' untranslated region of the poliovirus genome. Journal of Virology 74, 2219-26 (2000).
108. Pilipenko, E.V. et al. A cell cycle-dependent protein serves as a template-specific translation initiation factor. Genes and Development 14, 2028-45 (2000).
109. Shih, S.R., Stollar, V. & Li, M.L. Host factors in enterovirus 71 replication. J Virol 85, 9658-66 (2011).
110. Lin, J.Y. et al. Heterogeneous nuclear ribonuclear protein K interacts with the enterovirus 71 5' untranslated region and participates in virus replication. J Gen Virol 89, 2540-9 (2008).
111. Lin, J.Y. et al. hnRNP A1 interacts with the 5' untranslated regions of enterovirus 71 and Sindbis virus RNA and is required for viral replication. J Virol 83, 6106-14 (2009).
112. Chien, H.L., Liao, C.L. & Lin, Y.L. FUSE binding protein 1 interacts with untranslated regions of Japanese encephalitis virus RNA and negatively regulates viral replication. J Virol 85, 4698-706 (2011).
113. Lin, J.Y., Li, M.L. & Shih, S.R. Far upstream element binding protein 2 interacts with enterovirus 71 internal ribosomal entry site and negatively regulates viral translation. Nucleic Acids Res 37, 47-59 (2009).
114. Ragazzon, P.A., Garbett, N.C. & Chaires, J.B. Competition dialysis: a method for the study of structural selective nucleic acid binding. Methods 42, 173-82 (2007).
115. Gasparian, A.V. et al. Inhibition of encephalomyocarditis virus and poliovirus replication by quinacrine: implications for the design and discovery of novel antiviral drugs. J Virol 84, 9390-7 (2010).
116. Tyleckova, J. et al. Cancer cell response to anthracyclines effects: mysteries of the hidden proteins associated with these drugs. Int J Mol Sci 13, 15536-64 (2012).
117. Charak, S. & Mehrotra, R. Structural investigation of idarubicin-DNA interaction: spectroscopic and molecular docking study. Int J Biol Macromol 60, 213-8 (2013).
118. Gianni, L., Zweier, J.L., Levy, A. & Myers, C.E. Characterization of the cycle of iron-mediated electron transfer from Adriamycin to molecular oxygen. J Biol Chem 260, 6820-6 (1985).
119. Olson, R.D. & Mushlin, P.S. Doxorubicin cardiotoxicity: analysis of prevailing hypotheses. FASEB J 4, 3076-86 (1990).
120. Doroshow, J.H., Locker, G.Y. & Myers, C.E. Enzymatic defenses of the mouse heart against reactive oxygen metabolites: alterations produced by doxorubicin. J Clin Invest 65, 128-35 (1980).
121. Wouters, K.A., Kremer, L.C., Miller, T.L., Herman, E.H. & Lipshultz, S.E. Protecting against anthracycline-induced myocardial damage: a review of the most promising strategies. Br J Haematol 131, 561-78 (2005).
122. Krischer, J.P. et al. Clinical cardiotoxicity following anthracycline treatment for childhood cancer: the Pediatric Oncology Group experience. J Clin Oncol 15, 1544-52 (1997).
123. Ryberg, M. et al. Epirubicin cardiotoxicity: an analysis of 469 patients with metastatic breast cancer. J Clin Oncol 16, 3502-8 (1998).
124. Money-Kyrle, J.F. et al. Liposomal daunorubicin in advanced Kaposi's sarcoma: a phase II study. Clin Oncol (R Coll Radiol) 5, 367-71 (1993).
125. Hasinoff, B.B. The interaction of the cardioprotective agent ICRF-187 [+)-1,2-bis(3,5-dioxopiperazinyl-1-yL)propane); its hydrolysis product (ICRF-198); and other chelating agents with the Fe(III) and Cu(II) complexes of adriamycin. Agents Actions 26, 378-85 (1989).
126. Herman, E.H., Zhang, J., Hasinoff, B.B., Clark, J.R., Jr. & Ferrans, V.J. Comparison of the structural changes induced by doxorubicin and mitoxantrone in the heart, kidney and intestine and characterization of the Fe(III)-mitoxantrone complex. J Mol Cell Cardiol 29, 2415-30 (1997).
127. Solomon, T. et al. Virology, epidemiology, pathogenesis, and control of enterovirus 71. Lancet Infect Dis 10, 778-90 (2010).
128. Lin, J.Y. et al. Viral and host proteins involved in picornavirus life cycle. J Biomed Sci 16, 103 (2009).
129. Minor, P.D. Polio eradication, cessation of vaccination and re-emergence of disease. Nat Rev Microbiol 2, 473-82 (2004).
130. de Fougerolles, A., Vornlocher, H.P., Maraganore, J. & Lieberman, J. Interfering with disease: a progress report on siRNA-based therapeutics. Nat Rev Drug Discov 6, 443-53 (2007).
131. Tan, C.W., Lai, J.K., Sam, I.C. & Chan, Y.F. Recent developments in antiviral agents against enterovirus 71 infection. J Biomed Sci 21, 14 (2014).

連結至畢業學校之論文網頁點我開啟連結
註: 此連結為研究生畢業學校所提供,不一定有電子全文可供下載,若連結有誤,請點選上方之〝勘誤回報〞功能,我們會盡快修正,謝謝!
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top