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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 | Tzu-Chen Lin | en |
dc.contributor.author | 林子禎 | zh_TW |
dc.date.accessioned | 2021-06-15T13:32:43Z | - |
dc.date.available | 2021-02-24 | |
dc.date.copyright | 2016-02-24 | |
dc.date.issued | 2016 | |
dc.date.submitted | 2016-02-02 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/51393 | - |
dc.description.abstract | 流行性感冒為流感病毒造成的急性呼吸道疾病,是常見的傳染性疾病。季節性流感每年都會週期性的在人類間流行,並且隨著病毒的突變也會產生偶發性的嚴重大規模流行。流感病毒脂質包膜上的血液凝集素(hemagglutinin, HA)與神經胺酸酶(neuraminidase, NA)在病毒的致病機轉中扮演了重要的角色。由於神經胺酸酶擁有相對保守的活性中心,因此針對神經胺酸酶作用的抑制劑是非常重要的流感藥物。其中口服投藥的克流感(oseltamivir phosphate, TamifluTM)是最被廣泛用於治療的神經胺酸酶抑制劑。但隨著抗流感藥物的廣泛使用,對克流感具有抗藥性的病毒突變株大量出現,因此設計對於突變的流感病毒有抑制性的抑制劑成為重要課題。
由本實驗室與中研院基因體研究中心合作開發的單磷酯零流感(tamiphosphor monoester)以及其胍基類似物(guanidino tamiphosphor monoester),不但對於突變病毒株具有抑制性,也增進零流感的生體可用率。在本篇研究中,我們合成了胺基酸修飾的單磷酯零流感化合物32–34,以期能夠被細胞膜上的肽轉運蛋白PepT1 (peptide transporter 1)辨認,並接受其為受質協助其穿膜運輸,此策略的目的為藉由分佈於小腸上皮細胞的PepT1對藥物的傳輸加強口服生體可用率。 另外為了設計新型的抗流感神經胺酸酶抑制劑,我們挑選了peramivir (RapivabTM)作為核心結構。Peramivir目前被視為治療流感的最後手段,主要提供因昏迷無法口服或吸入其他抗病毒藥物的嚴重患者的治療。但是已知一些病毒突變株對peramivir也具中等抗藥性。為了解決這個問題,我們模仿神經胺酸脢天然受質唾液酸結構中的甘油基,設計了將peramivir結構中親脂性的3-戊基以鄰二醇取代的新抑制劑67,希望達到降低抗藥性的目的。 | zh_TW |
dc.description.abstract | Influenza is one of the most common infectious disease that causes seasonal epidemics and occasional global pandemics. Hemagglutinin and neuraminidase are two important membrane proteins that contribute to the pathogenicity of influenza virulence. Inhibitors against neuraminidase are particularly useful in the development of anti-influenza agents because the active sites of different neuraminidases are relatively conservative. Orally available oseltamivir phosphate (TamifluTM) is the most widely applied drug in clinical treatment among the neuraminidase inhibitors. Nevertheless, emergence of oseltamivir-resistant viruses demonstrates the need for novel inhibitor design. In our lab, we have developed a series of oseltamivir derivatives, such as the monoesters of phosphonate oseltamivir (tamiphosphor monoesters) and their guanidino analogues, to target mutant viruses with increased bioavailability. Substantial efforts are made in this work to synthesize amino acid derivatives of tamiphosphor monoesters 32–34 as a strategy to develop inhibitors with enhanced bioavailability utilizing the active transport of human peptide transporter (hPEPT1).
Peramivir (RapivabTM) is another FDA approved neuraminidase inhibitor that is considered as the last medication of influenza; however, some influenza viruses with moderate drug resistance also emerge. To tackle this problem, we thus designed an analogous compound 67 by altering the 3-pentyl side chain of peramivir to a glycol moiety that resembles the glycerol chain on sialic acid, a natural NA substrate. This compound is synthesized to test its anti-influenza activity, and hopefully its efficacy in inhibition of the drug-resistant strain will increase as our expectation. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T13:32:43Z (GMT). No. of bitstreams: 1 ntu-105-R02223225-1.pdf: 9207973 bytes, checksum: 96132deb4524a5d12fd3e41ae5e6da9c (MD5) Previous issue date: 2016 | en |
dc.description.tableofcontents | Chapter 1. INTRODUCTION OF INFLUENZA 1
1.1 Background 1 1.1.1 Pathophysiology 1 1.1.2 Etiology 2 1.1.3 Epidemiology 3 1.1.4 History of influenza 4 1.2 Influenza virus 6 1.2.1 The structure of influenza virus 6 1.2.2 Life cycle of influenza virus 7 1.2.3 Important membrane proteins of influenza virus 9 1.2.4 Other proteins of influenza virus 14 1.3 Medication 16 1.3.1 M2 ion channel inhibitors 16 1.3.2 Hemagglutinin inhibitors 17 1.3.3 Neuraminidase inhibitors 19 1.3.4 Vaccines and neutralizing antibodies 21 Chapter 2. DEVELOPEMENT OF INFLUENZA NEURAMINIDASE INHIBITORS 24 2.1 Mechanism of enzyme catalysis 24 2.2 Neuraminidase inhibitors used in clinical application: design, advantages and drawbacks 25 2.2.1 Zanamivir 27 2.2.2 Oseltamivir 29 2.2.3 Peramivir 32 2.3 Emerging issues for neuraminidase inhibitors 36 2.3.1 Mutant viruses and drug resistance 36 2.3.2 Bioavailability of neuraminidase inhibitors 39 2.4 Recent development and design of analogues of neuraminidase inhibitors 41 2.4.1 Zanamivir derivative as a long-acting drug: Laninamivir and its prodrug 41 2.4.2 Oseltamivir bioisosteres: Tamiphosphor and tamiphosphor monoesters 44 Chapter 3. DESIGN AND SYNTHESIS OF NEURAMINIDASE INHIBITORS WITH INCREASED BIOAVAILABILITY 52 3.1 Bioavailability: Introduction 52 3.2.1 Passive diffusion: increasing hydrophobicity 55 3.2.2 Active transport: carrier-mediated approach 57 3.3 Carrier-mediated transport via hPEPT1 58 3.3.1 The physiological role of peptide transporters 58 3.3.2 Substrate specificity 60 3.3.3 Researches exploiting PepT1 for enhanced drug bioavailability 61 3.4 Design of tamiphosphor monoester analogues for hPepT1 mediated transport 63 3.5 Results and discussion 67 3.5.1 Synthesis of target compounds 67 3.5.2 Enzymatic and anti-influenza assays 76 3.5.3 MDCK cellular uptake studies 79 3.6 Summary 84 Chapter 4. DESIGN AND SYNTHESIS OF PERAMIVIR ANALOGUES TARGETING INFLUENZA MUTANT VIRUS 86 4.1 Drug resistance of neuraminidase inhibitors 86 4.1.1 H274Y mutation 86 4.1.2 R292K mutation 89 4.1.3 E119G mutation 93 4.2 Design of peramivir analogues against mutant neuraminidase 96 4.3 Results and discussion 97 4.3.1 Synthesis of target peramivir analogue 67 97 4.4 Enzymatic and anti-influenza assays 117 4.5 Summary 118 Chapter 5. CONCLUSION AND PERSPECTIVE 120 Chapter 6. EXPERIMENTAL SECTION 123 5.1 General description 123 5.2 Procedures of bioassays 124 5.1.1 Material 124 5.1.2 Determination of influenza virus TCID50 125 5.1.3 Determination of IC50 of neuraminidase inhibitors 125 5.1.4 Determination of EC50 values 126 5.1.5 MDCK cellular uptake studies 127 5.1.6 Gly-Sar cellular uptake inhibition studies 128 5.3 Synthetic procedures and characterization of compounds 130 BIBLIOGRAPHY 165 APPENDIX A Nuclear magnetic resonance spectra and HPLC diagrams 178 APPENDIX B Experimental data of cellular uptake assay 218 | |
dc.language.iso | en | |
dc.title | 針對突變病毒設計與合成具有良好生體可用率之新型抗流感藥物 | zh_TW |
dc.title | Design and Synthesis of Novel Anti-Influenza Agents with Increased Bioavailability to Target Mutant Viruses | en |
dc.type | Thesis | |
dc.date.schoolyear | 104-1 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 林君榮,王宗興,謝俊結 | |
dc.subject.keyword | 流行性感冒病毒,神經胺酸?抑制劑,抗藥性,生體可用率,?轉運蛋白, | zh_TW |
dc.subject.keyword | influenza,neuraminidase inhibitor,drug-resistance,bioavailability,peptide transporter, | en |
dc.relation.page | 223 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2016-02-02 | |
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 |
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