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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 梁碧惠(Pi-Hui Liang) | |
dc.contributor.author | Hao-Wen Cheng | en |
dc.contributor.author | 鄭皓文 | zh_TW |
dc.date.accessioned | 2021-06-16T05:22:28Z | - |
dc.date.available | 2014-10-20 | |
dc.date.copyright | 2014-10-20 | |
dc.date.issued | 2014 | |
dc.date.submitted | 2014-08-15 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/56299 | - |
dc.description.abstract | 流感是由流感病毒造成的,到目前為止流感仍是全球性傳染的疾病。每年大約有500 萬人感染流感,而其中大約有50 萬人會死於流感。流感病毒的傳染力是由二種病毒表面糖蛋白所造成的,這二種醣蛋白分別是血球凝集素(HA)和神經胺酸酶(NA),而它們具有專一性的辨認人類宿主細胞上的特異性α2-6 的末端唾液酸(sialic acid),透過醣晶片量化分析顯示Neu5Acα(2-6)Galβ(1-4)GlcNAc(Glc) 此參醣分子已被確認和HA 的結合具有重要性,而近來的研究更顯示具有此參醣結構的唾液酸伍醣分子Neu5Acα(2-6)Galβ(1-4)GlcNAcβ(1-3)Galβ(1-4)-Glc-(or GlcNAc)可能更具重要性。抑制掉HA 和唾液酸的結合可能也是一種對抗流感的替代方式,而且目前也幾乎沒有這方面的研究。另一方面,由於NA 會切斷氧連結的唾液酸,因此用硫鍵結取代氧能使化合物更穩定。透過仔細的保護基控制反應的方式,我們透過[2+2+1]的合成策略,合成了硫鍵結伍醣分子Neu5Ac-α(2-6)-S-Gal-β(1-4)GlcNAc-β(1-3)Gal-β(1-4)lcNAc,此分子為第一次被合成出,在34 步的反應過程中總產率2.4%,且在可還原端具有乙醇酸的修飾可作為之後的連接。在分別接上DLPE 及HMPA 後做成微脂粒及微胞,而這二種都被設計為具多價效應的物質,可增加和流感病毒的HA 的作用力而增加抑制性。為了避免微脂粒被細胞胞吞作用,我們設計微脂粒大小小於200 奈米。另外,因為HA三聚體的本身單體距離,我們特意設計表面唾液酸五醣彼此間距離等同於HA 三聚體的本身單體的距離,而所需唾液酸伍醣分子的比例大約是0.8%。我們合成的硫鍵結唾液酸伍醣分子以及其微脂粒37-SL1, 37-SL2, 37-SL3 和微胞MC1 被用來測試抑制流感病毒A/WSN/33 H1N1 進入細胞能力的實驗,然而抑制效果都不盡理想,而後續的凝集素和唾液酸的作用力實驗也會用來評估此唾液酸伍醣的一個依據。 | zh_TW |
dc.description.abstract | Influenza caused by influenza virus is still fairly widespread disease. It is about five million people infected and about five hundred thousand infected people die every year. The infection power of influenza virus is related to the interaction of two viral glycoprotein, hemaglutinin (HA) and neuraminidase (NA), with specific terminal Neu5Ac-α(2-6)Gal linkage glycans of human membrane. Through the glycan arrays and protein co-crystal studies, glycan – Neu5Ac-α(2-6)Gal-β(1-4)GlcNAc has been identified to be the most important HA-binding glycans. Recent studies further proved that extension of two saccharide to pentasaccharide Neu5Acα(2-6)Galβ(1-4)GlcNAcβ(1-3)Galβ(1-4)Glc(orGlcNAc) known as sialyllacto-N-tetrasaccharide c (LSTc) was also critical important. Blocking HA is an alternatively potential option to inhibit virus-cell adhesion, so far only few studies working on HA inhibitions. Because NA cleaves O-sialoside rapidly in vivo, S-sialosideis potentially more stable bioisostere mimic of O-sialoside. Through carefully protective group manipulations, a S-linked LSTc (Neu5Ac-α(2-6)-S-Gal-β(1-4)GlcNAc-β(1-3)Gal-β(1-4)GlcNAc) with a glycolate handle at the reducing end was firstly synthesized (34 steps, 2.3% total yield) by a [2+2+1] strategy. After, glycolate handle was conjugated with DPLE to form liposome and with HMPA to form micelle. Both liposome and micelle were designed to display the S-linked LSTc in a multivalent format which was thought to be an important factor for HA to bind with sialic acid from human cell surface. To avoid liposome to be spontaneously uptake into cell by endocytosis, the diameter of liposome and micelle were designed to in a range of ≦200 nm. Since HA is trimer in nature, to get perfectly position of S-linked LSTc display on the liposome surface, it was calculated that 0.8 mol% of S-linked LSTc on liposome would be enough to enhance avidity.
The synthetic S-linked LSTc (9) and their liposomal form (37-SL1, 37-SL2, 37-SL3) and micelle form (MC1) were subjected to A/WSN/33 H1N1 influenza entry inhibition assay. However, all of these compounds/formulations were not able to inhibit influenza virus entry. Since these ligands were omogenously synthesized, it can be further used in the study of lectin-sialic acid interactions. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T05:22:28Z (GMT). No. of bitstreams: 1 ntu-103-R01423003-1.pdf: 13559637 bytes, checksum: 8dcbc4ca02daca3749c591555ef2411e (MD5) Previous issue date: 2014 | en |
dc.description.tableofcontents | 中文摘要....................................................................................................................... i
Abstract......................................................................................................................... iii Table of contents.......................................................................................................... .v List of Figures ..............................................................................................................vii List of Schemes.............................................................................................................viii List of Tables ................................................................................................................. ix List of Abbreviations .....................................................................................................x Chapter 1 - Introduction 1.1 Epidemiology of Influenza......................................................................................1. 1.1.1 Subtypes and pandemic of Influenza............................................................1. 1.2 Structures and Functions of Influenza......................................................................3 1.3 Hemagglutinin..........................................................................................................5 1.3.1 Structure and Functions of HA......................................................................5 1.3.2 Glycan Arrays by Influenza HA Recognition................................................8 1.4 Multivalent Effect...................................................................................................10 1.5S-linked Glycosides and its Applications.................................................................13 1.5.1S-linked Glycosides with Dendrimer as NA Inhibitors.................................13 1.6 Surface modification liposome and micelle……………………………………....14 1.7 Liposome encapsulated with Zanamivir in anti-influenza targeting………….…..15 1.8 Aim & Purposes.......................................................................................................16 Chapter 2 - Results 2.1 Strategy...................................................................................................................19 2.1.1 Retrosynthetic analysis.................................................................................19 2.1.2 Preparation of Galactose15 and 17..............................................................21. 2.1.3 Preparation of GluNAc derivatives 16 and 18………………………….…22 2.1.4 Gycosylation steps…………………………………………………….…..23 2.2 Preparation of Liposome.........................................................................................30 2.3 Preparation of Micelle.............................................................................................33 2.4 Preparation of Zanamivir encapsulated single layer liposome…………................33 2.5 Bioactivity…………………..………………………………………………….…34 2.5.1 Neutralization assay…………………………………………...……….…..34 2.5.2. Cytopathic assay……………………………………………………….….36 2.5.3. Hemagglutinin inhibition assay……………………………………..37 Chapter 3 –Conclusions…………………………………………………………..….39 Chapter 4 – Experimental Section………………………………………………..…42 4.1 General Information.................................................................................................42 4.2. General Procedure for Compounds Preparation......................................................44 4.3. General procedure for Biological Assay .................................................................64 4.3.1. Neutralization Assay.....................................................................................64 4.3.2. Cytopathic assay………………………………………………………..….65 4.3.3. Hemagglutinin inhibition assay……………………………………..66 4.4 Preparation of liposome…………………………………………………………...66 4.4.1 Preparation of single layer liposome…………..…………………………...66 4.4.2 Preparation of multilayer liposome……………………………….……...…67 4.4.3 Preparation of single layer liposome encapusulated Zanamivir……..…..…67 4.4.4 Preparation of micelle……………………………...………………………..67 References……………………………………………………………………………...69 Appendices (NMR Spectra)..........................................................................................77 | |
dc.language.iso | en | |
dc.title | 合成具唾液酸伍醣分子之微脂粒及其抗A型流感病毒的研究 | zh_TW |
dc.title | Study on Sialyllacto-N-tetrasaccharide c (LSTc)-bearing Liposomal Synthesis and Anti-influenza A Virus | en |
dc.type | Thesis | |
dc.date.schoolyear | 102-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 陳基旺(Ji-Wang Chern),忻凌偉(Ling-Wei Hsin),鄭義循(Yih-Shyun Cheng) | |
dc.subject.keyword | 唾液酸伍醣分子, | zh_TW |
dc.subject.keyword | LSTc, | en |
dc.relation.page | 107 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2014-08-15 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥學研究所 | zh_TW |
顯示於系所單位: | 藥學系 |
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