請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/76581完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 方俊民(Jim-Min Fang) | |
| dc.contributor.author | Din-Chi Chiu | en |
| dc.contributor.author | 邱鼎棋 | zh_TW |
| dc.date.accessioned | 2021-07-10T21:33:19Z | - |
| dc.date.available | 2021-07-10T21:33:19Z | - |
| dc.date.copyright | 2017-08-29 | |
| dc.date.issued | 2017 | |
| dc.date.submitted | 2017-06-27 | |
| dc.identifier.citation | 1. (a) Lowen, A.; Palese, P. Influenza virus transmission: basic science and implications for the use of antiviral drugs during a pandemic. Infect. Disord. Drug Targets 2007, 7, 318−328; (b) Taubenberger, J. K.; Morens, D. M. The pathology of influenza virus infections. Annu. Rev. Pathol. 2008, 3, 499−522.
2. Cox, N. J.; Subbarao, K. Global epidemiology of influenza: past and present. Annu. Rev. Med. 2000, 51, 407−421. 3. Morens, D. M.; Fauci, A. S. The 1918 influenza pandemic: insights for the 21st century. J. Infect. Dis. 2007, 195, 1018−1028. 4. Peiris, J. S.; Yu, W. C.; Leung, C. W.; Cheung, C. Y.; Ng, W. F.; Nicholls, J. M.; Ng, T. K.; Chan, K. H.; Lai, S. T.; Lim, W. L.; Yuen, K. Y.; Guan, Y. Re-emergence of fatal human influenza A subtype H5N1 disease. Lancet 2004, 363, 617−619. 5. Taubenberger, J. K.; Morens, D. M. 1918 influenza: the mother of all pandemics. Emerging Infect. Dis. 2006, 12, 15−22. 6. Bouvier, N. M.; Palese, P. The biology of influenza viruses. Vaccine 2008, 26 Suppl 4, D49−53. 7. Karlsson Hedestam, G. B.; Fouchier, R. A.; Phogat, S.; Burton, D. R.; Sodroski, J.; Wyatt, R. T. The challenges of eliciting neutralizing antibodies to HIV-1 and to influenza virus. Nat. Rev. Microbiol. 2008, 6, 143−155. 8. Min, J. Y.; Subbarao, K. Cellular targets for influenza drugs. Nat. Biotech. 2010, 28, 239−240. 9. Samji, T. Influenza A: understanding the viral life cycle. Yale J. Biol. Med. 2009, 82, 153−159. 10. von Itzstein, M. The war against influenza: discovery and development of sialidase inhibitors. Nat. Rev. Drug Discov. 2007, 6, 967−974. 11. (a) Skehel, J. J.; Wiley, D. C. Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin. Annu. Rev. Biochem. 2000, 69, 531−569; (b) Suzuki, Y. Sialobiology of influenza: molecular mechanism of host range variation of influenza viruses. Biol. Pharm. Bull. 2005, 28, 399−408. 12. (a) Gamblin, S. J.; Skehel, J. J. Influenza hemagglutinin and neuraminidase membrane glycoproteins. J. Biol. Chem. 2010, 285, 28403−28409; (b) Russell, R. J.; Kerry, P. S.; Stevens, D. J.; Steinhauer, D. A.; Martin, S. R.; Gamblin, S. J.; Skehel, J. J. Structure of influenza hemagglutinin in complex with an inhibitor of membrane fusion. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 17736−17741; (c) Das, K.; Aramini, J. M.; Ma, L. C.; Krug, R. M.; Arnold, E. Structures of influenza A proteins and insights into antiviral drug targets. Nat. Struct. Mol. Biol. 2010, 17, 530−538. 13. (a) Pinto, L. H.; Lamb, R. A. The M2 proton channels of influenza A and B viruses. J. Biol. Chem. 2006, 281, 8997−9000; (b) Schnell, J. R.; Chou, J. J. Structure and mechanism of the M2 proton channel of influenza A virus. Nature 2008, 451, 591−595. 14. (a) Air, G. M. Influenza neuraminidase. Influenza Other Respir. Viruses 2012, 6, 245−256; (b) Shtyrya, Y. A.; Mochalova, L. V.; Bovin, N. V. Influenza virus neuraminidase: structure and function. Acta Naturae 2009, 1, 26−32. 15. Taylor, N. R.; von Itzstein, M. Molecular modeling studies on ligand binding to sialidase from influenza virus and the mechanism of catalysis. J. Med. Chem. 1994, 37, 616−624. 16. Bodian, D. L.; Yamasaki, R. B.; Buswell, R. L.; Stearns, J. F.; White, J. M.; Kuntz, I. D. Inhibition of the fusion-inducing conformational change of influenza hemagglutinin by benzoquinones and hydroquinones. Biochemistry 1993, 32, 2967−2978. 17. (a) Stiver, G. The treatment of influenza with antiviral drugs. Can. Med. Assoc. J. 2003, 168, 49–57; (b) Pielak, R. M.; Schnell, J. R.; Chou, J. J. Mechanism of drug inhibition and drug resistance of influenza A M2 channel. Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 737−784. 18. Cady, S. D.; Schmidt-Rohr, K.; Wang, J.; Soto, C. S.; Degrado, W. F.; Hong, M. Structure of the amantadine binding site of influenza M2 proton channels in lipid bilayers. Nature 2010, 463, 689−692. 19. Thomaston, J. L.; DeGrado, W. F. Crystal structure of the drug-resistant S31N influenza M2 proton channel. Protein Sci. 2016, 25, 1551−1554. 20. Meindl, P.; Bodo, G.; Palese, P.; Schulman, J.; Tuppy, H. Inhibition of neuraminidase activity by derivatives of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid. Virology 1974, 58, 457−463. 21. Bossart-Whitaker, P.; Carson, M.; Babu, Y. S.; Smith, C. D.; Laver, W. G.; Air, G. M. Three-dimensional structure of influenza A N9 neuraminidase and its complex with the inhibitor 2-deoxy 2,3-dehydro-N-acetyl neuraminic acid. J. Mol. Biol. 1993, 232, 1069−1083. 22. von Itzstein, M.; Wu, W. Y.; Kok, G. B.; Pegg, M. S.; Dyason, J. C.; Jin, B.; Van Phan, T.; Smythe, M. L.; White, H. F.; Oliver, S. W.; et al. Rational design of potent sialidase-based inhibitors of influenza virus replication. Nature 1993, 363, 418−423. 23. (a) Elliott, M. Zanamivir: from drug design to the clinic. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2001, 356, 1885−1893; (b) Dunn, C. J.; Goa, K. L. Zanamivir - A review of its use in influenza. Drugs 1999, 58, 761−784. 24. Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H.; Zhang, L.; Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Mendel, D. B.; Tai, C. Y.; Laver, W. G.; Stevens, R. C. Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity. J. Am. Chem. Soc. 1997, 119, 681−690. 25. Kim, C. U.; Lew, W.; Williams, M. A.; Wu, H.; Zhang, L.; Chen, X.; Escarpe, P. A.; Mendel, D. B.; Laver, W. G.; Stevens, R. C. Structure-activity relationship studies of novel carbocyclic influenza neuraminidase inhibitors. J. Med. Chem. 1998, 41, 2451−2460. 26. Sidwell, R. W.; Huffman, J. H.; Barnard, D. L.; Bailey, K. W.; Wong, M. H.; Morrison, A.; Syndergaard, T.; Kim, C. U. Inhibition of influenza virus infections in mice by GS4104, an orally effective influenza virus neuraminidase inhibitor. Antiviral Res. 1998, 37, 107−120. 27. Sweeny, D. J.; Lynch, G.; Bidgood, A. M.; Lew, W.; Wang, K. Y.; Cundy, K. C. Metabolism of the influenza neuraminidase inhibitor prodrug oseltamivir in the rat. Drug Metab. Dispos. 2000, 28, 737−741. 28. Davies, B. E. Pharmacokinetics of oseltamivir: an oral antiviral for the treatment and prophylaxis of influenza in diverse populations. J. Antimicrob. Chemother. 2010, 65 Suppl 2, ii5−ii10. 29. Yamamoto, T.; Kumazawa, H.; Inami, K.; Teshima, T.; Shiba, T. Syntheses of sialic acid isomers with inhibitory activity against neuraminidase. Tetrahedron Lett. 1992, 33, 5791−5794. 30. Babu, Y. S.; Chand, P.; Bantia, S.; Kotian, P.; Dehghani, A.; El-Kattan, Y.; Lin, T. H.; Hutchison, T. L.; Elliott, A. J.; Parker, C. D.; Ananth, S. L.; Horn, L. L.; Laver, G. W.; Montgomery, J. A. BCX-1812 (RWJ-270201): Discovery of a novel, highly potent, orally active, and selective influenza neuraminidase inhibitor through structure-based drug design. J. Med. Chem. 2000, 43, 3482−3486. 31. Alame, M. M.; Massaad, E.; Zaraket, H. Peramivir: a novel intravenous neuraminidase inhibitor for treatment of acute influenza infections. Front. Microbiol. 2016, 7, 450. 32. McLaughlin, M. M.; Skoglund, E. W.; Ison, M. G. Peramivir: an intravenous neuraminidase inhibitor. Expert Opin. Pharmacother. 2015, 16, 1889−1900. 33. (a) Belshe, R. B. The origins of pandemic influenza—lessons from the 1918 virus. N. Engl. J. Med. 2005, 353, 2209−2211; (b) De Clercq, E. Antiviral agents active against influenza A viruses. Nat. Rev. Drug Discov. 2006, 5, 1015−1025. 34. Hurt, A. C.; Ernest, J.; Deng, Y. M.; Iannello, P.; Besselaar, T. G.; Birch, C.; Buchy, P.; Chittaganpitch, M.; Chiu, S. C.; Dwyer, D.; Guigon, A.; Harrower, B.; Kei, I. P.; Kok, T.; Lin, C.; McPhie, K.; Mohd, A.; Olveda, R.; Panayotou, T.; Rawlinson, W.; Scott, L.; Smith, D.; D'Souza, H.; Komadina, N.; Shaw, R.; Kelso, A.; Barr, I. G. Emergence and spread of oseltamivir-resistant A(H1N1) influenza viruses in Oceania, South East Asia and South Africa. Antiviral Res. 2009, 83, 90−93. 35. Hurt, A. C.; Holien, J. K.; Parker, M. W.; Barr, I. G. Oseltamivir resistance and the H274Y neuraminidase mutation in seasonal, pandemic and highly pathogenic influenza viruses. Drugs 2009, 69, 2523−2531. 36. Hai, R.; Schmolke, M.; Leyva-Grado, V. H.; Thangavel, R. R.; Margine, I.; Jaffe, E. L.; Krammer, F.; Solorzano, A.; Garcia-Sastre, A.; Palese, P.; Bouvier, N. M. Influenza A(H7N9) virus gains neuraminidase inhibitor resistance without loss of in vivo virulence or transmissibility. Nat. Commun. 2013, 4, 2854. 37. Woods, C. J.; Malaisree, M.; Long, B.; McIntosh-Smith, S.; Mulholland, A. J. Computational assay of H7N9 influenza neuraminidase reveals R292K mutation reduces drug binding affinity. Sci. Rep. 2013, 3, 3561. 38. Yamashita, M.; Tomozawa, T.; Kakuta, M.; Tokumitsu, A.; Nasu, H.; Kubo, S. CS-8958, a prodrug of the new neuraminidase inhibitor R-125489, shows long-acting anti-influenza virus activity. Antimicrob. Agents Chemother. 2009, 53, 186−192. 39. Yamashita, M. Laninamivir and its prodrug, CS-8958: long-acting neuraminidase inhibitors for the treatment of influenza. Antivir. Chem. Chemother. 2010, 21, 71−84. 40. Ikematsu, H.; Kawai, N. Laninamivir octanoate: a new long-acting neuraminidase inhibitor for the treatment of influenza. Expert Rev. Anti Infect. Ther. 2011, 9, 851−857. 41. (a) Shie, J. J.; Fang, J. M.; Wang, S. Y.; Tsai, K. C.; Cheng, Y. S.; Yang, A. S.; Hsiao, S. C.; Su, C. Y.; Wong, C. H. Synthesis of tamiflu and its phosphonate congeners possessing potent anti-influenza activity. J. Am. Chem. Soc. 2007, 129, 11892−11893; (b) Cheng, T. J.; Weinheimer, S.; Tarbet, E. B.; Jan, J. T.; Cheng, Y. S.; Shie, J. J.; Chen, C. L.; Chen, C. A.; Hsieh, W. C.; Huang, P. W.; Lin, W. H.; Wang, S. Y.; Fang, J. M.; Hu, O. Y.; Wong, C. H. Development of oseltamivir phosphonate congeners as anti-influenza agents. J. Med. Chem. 2012, 55, 8657−8670. 42. Chen, C. L.; Lin, T. C.; Wang, S. Y.; Shie, J. J.; Tsai, K. C.; Cheng, Y. S.; Jan, J. T.; Lin, C. J.; Fang, J. M.; Wong, C. H. Tamiphosphor monoesters as effective anti-influenza agents. Eur. J. Med. Chem. 2014, 81, 106−118. 43. Shie, J. J.; Fang, J. M.; Lai, P. T.; Wen, W. H.; Wang, S. Y.; Cheng, Y. S.; Tsai, K. C.; Yang, A. S.; Wong, C. H. A practical synthesis of zanamivir phosphonate congeners with potent anti-influenza activity. J. Am. Chem. Soc. 2011, 133, 17959−17965. 44. Wang, P. C.; Fang, J. M.; Tsai, K. C.; Wang, S. Y.; Huang, W. I.; Tseng, Y. C.; Cheng, Y. S. E.; Cheng, T. J. R.; Wong, C. H. Peramivir phosphonate derivatives as influenza neuraminidase inhibitors. J. Med. Chem. 2016, 59, 5297−5310. 45. Chand, P.; Kotian, P. L.; Dehghani, A.; El-Kattan, Y.; Lin, T. H.; Hutchison, T. L.; Babu, Y. S.; Bantia, S.; Elliott, A. J.; Montgomery, J. A. Systematic structure-based design and stereoselective synthesis of novel multisubstituted cyclopentane derivatives with potent antiinfluenza activity. J. Med. Chem. 2001, 44, 4379-4392. 46. Andre, C.; Bolte, J.; Demuynck, C. Syntheses of L-threose and D-erythrose analogues modified at position 2. Tetrahedron: Asymmetry 1998, 9, 1359−1367. 47. Flynn, D. L.; Zelle, R. E.; Grieco, P. A. A mild two-step method for the hydrolysis of lactams and secondary amides. J. Org. Chem. 1983, 48, 2424−2426. 48. Wang, J.; Liang, Y. L.; Qu, J. Boiling water-catalyzed neutral and selective N-Boc deprotection. Chem. Commun. 2009, 5144-5146. 49. Mattsson, S.; Dahlström, M.; Karlsson, S. A mild hydrolysis of esters mediated by lithium salts. Tetrahedron Lett. 2007, 48, 2497−2499. 50. Nicolaou, K. C.; Estrada, A. A.; Zak, M.; Lee, S. H.; Safina, B. S. A mild and selective method for the hydrolysis of esters with trimethyltin hydroxide. Angew. Chem. Int. Ed. 2005, 44, 1378−1382. 51. Jia, F.; Hong, J.; Sun, P.-H.; Chen, J.-X.; Chen, W.-M. Facile synthesis of the neuraminidase inhibitor peramivir. Synth. Commun. 2013, 43, 2641−2647. 52. (a) Santra, A.; Ghosh, T.; Misra, A. K. Removal of benzylidene acetal and benzyl ether in carbohydrate derivatives using triethylsilane and Pd/C. Beilstein J. Org. Chem. 2013, 9, 74−78; (b) Mandal, P. K.; McMurray, J. S. Pd−C-induced catalytic transfer hydrogenation with triethylsilane. J. Org. Chem. 2007, 72, 6599−6601. 53. Wuts, P. G. M.; Greene, T. W., Greene's Protective Groups in Organic Synthesis, Fourth Edition. John Wiley & Sons, Inc.: 2007. 54. (a) Reed, L. J.; Muench, H. A Simple Method of Estimating Fifty Per Cent Endpoints12. Am. J. Epidemiol. 1938, 27, 493−497; (b) Burleson, F. G.; ChamBers, T. M.; Wiedbrauk, D. L., Virology, a Laboratory Manual. Academic Press: San Diago, CA, 1992. 55. Schmidt, P. M.; Attwood, R. M.; Mohr, P. G.; Barrett, S. A.; McKimm-Breschkin, J. L. A generic system for the expression and purification of soluble and stable influenza neuraminidase. PLoS One 2011, 6, e16284. 56. Dahlgren, A.; Kvarnstrom, I.; Vrang, L.; Hamelink, E.; Hallberg, A.; Rosenquist, A.; Samuelsson, B. Solid-phase library synthesis of reversed-statine type inhibitors of the malarial aspartyl proteases plasmepsin I and II. Bioorg. Med. Chem. 2003, 11, 827–841. 57. Tian, J.; Zhong, J.; Li, Y.; Ma, D. Organocatalytic and scalable synthesis of the anti-influenza drugs zanamivir, laninamivir, and CS-8958. Angew. Chem. Int. Ed. 2014, 53, 13885–13888. 58. Kudoh, T.; Fukuoka, M.; Ichikawa, S.; Murayama, T.; Ogawa, Y.; Hashii, M.; Higashida, H.; Kunerth, S.; Weber, K.; Guse, A. H.; Potter, B. V. L.; Matsuda, A.; Shuto, S. Synthesis of stable and cell-type selective analogues of cyclic ADP-ribose, a Ca2+-mobilizing second messenger. Structure-activity relationship of the N1-ribose moiety. J. Am. Chem. Soc. 2005, 127, 8846–8855. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/76581 | - |
| dc.description.abstract | 流行性感冒至今仍為一嚴重的公眾議題，並持續影響大眾衛生及健康。虧得眾多化學家之諸多貢獻，現今已有瑞樂沙、克流感及帕拉米弗等以不同投藥方式使用的神經胺酸酶抑制劑，且已成為針對流感最主要亦最有效的藥物。但由於這類藥物的抗藥性問題已經浮出檯面並日漸頻繁，嚴重影響了神經胺酸酶抑制劑的療效，也點出了研發新型流感藥物的急迫性。所以，以這些抑制劑與突變病毒株之神經胺酸酶的共結晶為基礎，我們設計出一系列具備親水性側鏈之帕拉米弗衍生物，企圖克服目前已發現因突變而引起的抗藥性問題。在合成方面，我們利用異抗壞血酸來製備1,3-偶集體氧化腈，而引入親水側鏈上的手性中心，並且開發出一個進行1,3-偶極環加成反應的新方法來製備關鍵中間物異噁唑，以建構帕拉米弗衍生物之主架構。其與傳統方法相較，需要較少之1,3-偶極體氧化腈且能有較高的立體選擇性。經大刀闊斧地延伸分子架構後，我們成功合成了四個帶有親水性側鏈的帕拉米弗衍生物。除了合成路徑開發的成功，我們所製備的衍生物皆具有不錯的抑制活性，且用於對抗突變病毒株時，也可觀測到抗藥性大幅緩解，此研究結果可啟發我們產出更優良的神經胺酸酶抑制劑。 | zh_TW |
| dc.description.abstract | So far, influenza remains to be a major problem and impact public health greatly. Thanks to many efforts of chemists, a number of neuraminidase inhibitors such us zanamivir, oseltamivir and peramivir have been developed and have become most widely used drugs in clinical treatments of influenza infections by different administrations. However, certain resistance has been observed and becoming common, thus leading to suppression of drug efficacies. The emergence of drug resistance reminds the urgency of discovering novel inhibitors.
Based on the results acquired from the cocrystal of inhibitors in mutant NA, we designed peramivir derivatives bearing various hydrophilic side chains in order to conquer problems of drug resistance. In the phase of synthesis, we employed D-(–)-isoascorbic acid to prepare nitrile oxide 1,3-dipole and introduce the chirality of hydrophilic side chain. In addition, a pioneering method with complete consumption of the dipolariphile was developed by using reduced amount of nitrile oxide 1,3-dipole to conduct the cycloaddition reaction for syntheses of isoxazolines, which are key intermediates to establish the scaffold of peramivir analogs, with enhanced stereoselectivity. After extensive derivatizations, we successfully synthesized four peramivir analogues carrying hydrophilic side chains. Aside from discovery of an alternative synthetic route, our synthetic candidate compounds demonstrated fairly good biological activity and alleviated drug resistance. These results may inspire us to produce better inhibitors. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-10T21:33:19Z (GMT). No. of bitstreams: 1 ntu-106-R04223117-1.pdf: 9071986 bytes, checksum: 03391506d89417375daaeb5f5eb020a3 (MD5) Previous issue date: 2017 | en |
| dc.description.tableofcontents | ABSTRACT IN CHINESE I
ABSTRACT IN ENGLISH II TABLE OF CONTENTS IV LIST OF FIGURES VIII LIST OF TABLES X LIST OF SCHEMES XI ABBREVIATIONS XII CHAPTER 1. INTRODUCTION 1 1.1 Overview 1 1.1.1 Pathology 1 1.1.2 History of influenza 1 1.2 Influenza virus 3 1.2.1 The structure of influenza A virus 3 1.2.2 Replication cycle of influenza virus 5 1.2.3 Envelope proteins of influenza virus 7 1.2.3.1 Hemagglutinin (HA) 7 1.2.3.2 Matrix protein 2 (M2 ion channel) 8 1.2.3.3 Neuraminidase (NA) 9 1.3 Medications for influenza 11 1.3.1 Hemagglutinin inhibitors 12 1.3.2 M2 protein inhibitors 13 1.3.3 Neuraminidase inhibitors 15 1.3.3.1 DANA 15 1.3.3.2 Zanamivir (ZA) 17 1.3.3.3 Oseltamivir (OS) 18 1.3.3.4 Peramivir (PE) 21 1.4 Viral resistance of neuraminidase inhibitors 23 1.4.1 Mechanisms of mutations 24 1.4.2 Various NA mutations 25 1.4.2.1 H275Y mutation 26 1.4.2.2 R292K mutation 27 1.5 Recent efforts on developments of novel neuraminidase inhibitors 29 1.5.1 Laninamivir (LA) 29 1.5.2 Phosphonate congeners of neuraminidase inhibitors 30 1.6 Methods to measure biological activity 34 CHAPTER 2. RESULTS AND DISCUSSION 37 2.1 Design of NAIs conquering viral resistance 37 2.2 Synthetic plan for peramivir derivatives 38 2.3 Syntheses of peramivir derivatives 39 2.3.1 Synthesis of target compound 28 39 2.3.2 Synthesis of target compound 30 55 2.3.3 Synthesis of target compound 29 58 2.3.4 Synthesis of target compound 27 64 2.4 Evaluations and analyses of biological activity 67 2.5 Conclusion and perspectives 69 CHAPTER 3. EXPERIMENTAL SECTION 71 3.1 General part 71 3.2 Procedure of bioassay 72 3.2.1. Material and methods 72 3.2.2 Determination of influenza virus TCID50 73 3.2.3 Cloning, expression, and purification of Influenza neuraminidases (NAs) 73 3.2.4 Determination of neuraminidase activity by a fluorescent assay 74 3.2.5 Determination of IC50 of NA inhibitor 75 3.2.6 Determination of EC50 and CC50 of NA inhibitor 75 3.3 Synthetic procedures and characterization of compounds 76 CHAPTER 4. REFERENCES 109 APPENDIX 120 | |
| dc.language.iso | en | |
| dc.title | 以具備親水性取代基之帕拉米弗衍生物克服流感病毒的抗藥性問題 | zh_TW |
| dc.title | Peramivir Analogues Bearing Hydrophilic Substituents to Overcome Influenza Viral Resistance | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 105-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 汪根欉(Ken-Tsung Wong),王宗興(Tsung-Shing Wang),謝俊結(Jiun-Jie Shie) | |
| dc.subject.keyword | 流行性感冒,神經胺酸?抑制劑,突變流感病毒,抗藥性, | zh_TW |
| dc.subject.keyword | Influenza,neuraminidase inhibitor,mutant influenza virus,drug resistance, | en |
| dc.relation.page | 177 | |
| dc.identifier.doi | 10.6342/NTU201701070 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2017-06-28 | |
| dc.contributor.author-college | 理學院 | zh_TW |
| dc.contributor.author-dept | 化學研究所 | zh_TW |
| 顯示於系所單位： | 化學系 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-106-R04223117-1.pdf 目前未授權公開取用 | 8.86 MB | Adobe PDF |
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。