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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/73463完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 方俊民 | |
| dc.contributor.author | Chi-Jiun Peng | en |
| dc.contributor.author | 彭啟鈞 | zh_TW |
| dc.date.accessioned | 2021-06-17T07:36:20Z | - |
| dc.date.available | 2024-04-19 | |
| dc.date.copyright | 2019-04-19 | |
| dc.date.issued | 2019 | |
| dc.date.submitted | 2019-04-15 | |
| dc.identifier.citation | 1. Antibiotic Resistance Threats in the United States, 2013. CDC. U.S. Department of Health & Human Services 2013.
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J., Some Aspects of the Chromogen 3,3',5,5'-Tetramethylbenzidine as Hydrogen Donor in a Horseradish-Peroxidase Assay. J. Clin. Chem. Clin. Biochem. 1989, 27 (10), 791-796. 145. Orenstein, W. A.; Bernier, R. H.; Dondero, T. J.; Hinman, A. R.; Marks, J. S.; Bart, K. J.; Sirotkin, B., Field evaluation of vaccine efficacy. Bull. W. H. O. 1985, 63 (6), 1055-1068. 146. King, N. P.; Bale, J. B.; Sheffler, W.; McNamara, D. E.; Gonen, S.; Gonen, T.; Yeates, T. O.; Baker, D., Accurate design of co-assembling multi-component protein nanomaterials. Nature 2014, 510 (7503), 103-108. 147. Peng, C. J.; Chen, H. L.; Chiu, C. H.; Fang, J. M., Site-selective functionalization of flagellin by steric self-protection: a strategy to facilitate flagellin as a self-adjuvanting carrier in conjugate vaccine. ChemBioChem 2018, 19 (8), 805-814. 148. Asakura, S.; Eguchi, G.; Iino, T., Reconstitution of bacterial flagella in vitro. J. Mol. Biol. 1964, 10 (1), 42-56. 149. Bewick, V.; Cheek, L.; Ball, J., Statistics review 12: survival analysis. Crit. Care 2004, 8 (5), 389-394. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/73463 | - |
| dc.description.abstract | 細菌鞭毛蛋白 (flagellin, FliC) 可以作為共軛疫苗 (conjugate vaccine) 載運抗原的載體蛋白，亦為類鐸受體 (toll-like receptor 5, TLR5) 之配位體，可以透過其自佐劑 (self-adjuvnat) 活性有效提高疫苗效力。鞭毛蛋白的佐劑效力來自其 D1 結構域與 TLR5 辨識結合後，再由 D0 結構域負責活化後續的訊息傳遞鏈。若以傳統不具位置選擇性的化學方法連結標的抗原與鞭毛載體生產共軛疫苗，結果將導致 D0 與 D1 結構域的過度修飾，造成鞭毛共軛產物 (conjugates) 喪失其佐劑活性。為使鞭毛蛋白能夠有效作為自佐劑載體，本研究首先利用鞭毛單體聚合鞭毛絲時產生的立體自我保護效應 (steric self-protection effect)，開發一個具有位置選擇性的化學修飾方法 (site-selective modification, SSM)，選擇性地於鞭毛蛋白中的 D2 與 D3 結構域建構生物正交官能基 (bioorthogonal groups) 以供後續抗原結合之用，有效避免 D0 和 D1 結構域的過度修飾，保留了鞭毛蛋白之自佐劑活性。
革蘭氏陰性菌表面具有獨特的脂多醣 (lipopolysaccharides, LPS)。這些具有輕度免疫原性的多醣是疫苗的合適抗原。本研究的第二個目的是利用去脂多醣 (lipid-A free LPS, LFPS) 結合前述細菌鞭毛蛋白，製備並評估一個新型抗傷寒沙門氏菌共軛疫苗。我們透過使用碘促進去羧基醯胺化反應 (iodine-promoted decarboxylative amidation) 與無痕跡 Staudinger 連接 (traceless Staudinger ligation)，運用不同的連結分子製備了三種保留了自佐劑活性的 stLFPS-stFliC 共軛疫苗(11)、(12)與(13)。動物實驗結果表明，以三種不同的共軛疫苗免疫的小鼠均能產生對脂多醣和鞭毛蛋白的特異性免疫反應。而用來連接去脂多醣和鞭毛蛋白的連結分子則不具有明顯的免疫原性。施打疫苗顯著延長了小鼠的存活時間並提升了存活率，這可能說明了 stLFPS-stFliC 共軛產物的自佐劑活性和多抗原表位特性確實如預期提高了疫苗效力。本研究的結果為開發具有自佐劑活性的 LFPS-FliC 共軛疫苗提供了可行的方法，並對疫苗發展提供了另外一個具有潛力的方向。 | zh_TW |
| dc.description.abstract | Flagellin (FliC) can act as a carrier protein in the preparation of conjugate vaccines and as an intrinsic adjuvant to activate the toll-like receptor 5 (TLR5) to enhance vaccine potency. The adjuvant activity of flagellin is derived from the binding of the D1 domain to TLR5 recognition site along with the subsequent signaling cascades activated by D0 domain. If a conventional conjugation method is used to link antigens to flagellin to produce a conjugate vaccine, over-modification of the D0 and D1 domains will result in the loss of adjuvant activity of the conjugate. To enable the use of FliC as a self-adjuvanting carrier, a site-selective modification (SSM) method based on the steric self-protection effect produced by the assembling of flagellin monomers to flagellar filaments is explored. This method selectively constructs bioorthogonal groups on the pertinent amino-acid residues in the D2 and D3 domains of FliC without excessive modification of the D0 and D1 domains, effectively retains the self-adjuvant activity of the flagellin.
Gram-negative bacteria exhibit unique lipopolysaccharide (LPS) on their surface. These accessible polysaccharides with mild immunogenicity are an appealing target for vaccination. Therefore, the second aim of this research is to prepare and evaluate an advanced conjugate vaccine against Salmonella typhimurium. Three self-adjuvanting stLFPS-stFliC conjugates (11), (12) and (13) were prepared through iodine-promoted decarboxylative amidation and traceless Staudinger ligation. Animal experiments showed that mice immunized with three different stLFPS-stFliC vaccines produced a significant immune response specific for lipopolysaccharide and flagellin of S. typhimurium. Meanwhile, the linker molecules are not significantly immunogenic. The vaccines significantly prolonged the survival time of mice and increased the survival rate, which may indicate that the self-adjuvanting ability and multiple epitopes of stLFPS-stFliC conjugates both provide immunity, as expected to improve the vaccine efficacy. The results of this research provide a viable approach to develop LFPS-FliC conjugate vaccines with self-adjuvant activity and offer a potential option for vaccine development. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T07:36:20Z (GMT). No. of bitstreams: 1 ntu-108-D03223205-1.pdf: 10254153 bytes, checksum: c986d47d62bea81123c12c40cfa86e99 (MD5) Previous issue date: 2019 | en |
| dc.description.tableofcontents | 口試委員會審定書 i
中文摘要 ii Abstract iii List of Figures xi List of Schemes xv List of Tables xvii List of Abbreviations xxi Chapter 1 Introduction 1 1.1 Hapten conjugate vaccines 1 1.2 Protein carriers and conjugation methods 4 1.2.1 Protein carriers of conjugate vaccines 4 1.2.2 Toll-like receptors 7 1.2.3 Flagellin as adjuvanting immunogen 9 1.2.4 Site-selective strategies for chemical modification of protein 10 1.2.5 Site-selective modification of flagellin by steric self-protection effect 13 1.3 Carbohydrate haptens 17 1.3.1 Cluster effect of carbohydrate haptens for multivalent carbohydrate-protein interactions 17 1.3.2 Lipopolysaccharides 19 1.3.3 Multi-epitopes lipopolysaccharide-based conjugate vaccine 22 1.4 Multivalent polysaccharide-flagellin conjugate vaccine 25 1.5 Treatment of Salmonella typhimurium 29 1.6 Scope of this thesis 29 Chapter 2 Results and Discussion 31 Section I: Site-Selective Modification 31 2.1 Synthesis of imidazole-1-sulfonyl azide hydrochloride 31 2.2 Synthesis of propargyl maltoside 32 2.3 Preparation of azido- and maltoside-modified FliC 33 2.4 Flagellin assembling and stability of flagellar assembly in chemical modification 36 2.5 Locations of lysine residues and quantitative analysis: site-selective modification versus nonselective modification 40 2.6 Reassembling of azido-modified flagellin monomers 48 2.7 Human toll-like receptor (hTLR5) activation 53 2.8 Advanced cross-strain platform for production of self-adjuvant carriers 57 Section II: LFPS-Flagellin Conjugate Vaccine 61 2.9 Synthesis of S-(diphenylphosphino)methanethiol borane complex 61 2.10 Synthesis of lysine-rich peptide S-(diphenylphosphino)methanethiolate as a linker in traceless Staudinger ligation 62 2.11 Synthesis of S-((diphenylphosphino)methyl) 6-aminohexanethioate as a linker in traceless Staudinger ligation 65 2.12 Preparation of LFPS-flagellin conjugate self-adjuvanting vaccines 66 2.13 Preparation of linker-BSA conjugates 75 2.14 hTLR5 activation of LFPS-flagellin conjugate self-adjuvanting vaccines 78 2.15 Immunogenicity of LFPS-flagellin conjugate vaccines 80 2.16 Antibacterial efficacy of LFPS-flagellin conjugate self-adjuvanting vaccines 87 Chapter 3 Conclusion and Prospects 97 Chapter 4 Experimental Section 99 4.1 General information, material and instrumentation 99 4.2 Synthetic procedures and compound characterization 101 4.2.1 Imidazole-1-sulfonyl azide hydrochloride (1-HCl) 101 4.2.2 Propargyl maltoside (15) 102 4.2.3 Tert-butyl (6-((2-nitrophenyl)sulfonamido)hexyl)carbamate (35) 102 4.2.4 N-(6-Aminohexyl)-2-nitrobenzenesulfonamide (4) 103 4.2.5 Bis(4-nitrophenyl) adipate (7) 104 4.2.6 S-Bromomethyl ethanethioate (20) 105 4.2.7 S-((Diphenylphosphaneyl)methyl) ethanethioate borane complex (21) 105 4.2.8 Diphenylphosphinomethanethiol borane complex (22) 106 4.2.9 Boc-protected lysine-rich peptide Boc-K(Boc)GK(Boc)GK(Boc)GGG-OH (24) 107 4.2.10 S-(Diphenylphosphino)methanethiolate borane complex of lysine-rich peptide (25) 108 4.2.11 S-(Diphenylphosphino)methanethiolate of lysine-rich peptide K3G5/SCH2PPh2 (9) 109 4.2.12 6-((Tert-butoxycarbonyl)amino)hexanoic acid (27) 109 4.2.13 S-((Diphenylphosphanyl)methyl) 6-((tert-butoxycarbonyl)amino) hexanethioate borane complex (28) 110 4.2.14 S-((Diphenylphosphanyl)methyl) 6-aminohexanethioate, C6/SCH2PPh2 (29) 111 4.3 Assembling of flagellin to flagellar filaments 111 4.4 Preparation of azido modified flagellar filament and flagellin monomer 112 4.5 Preparation of maltoside-modified paFliC by click reaction 114 4.6 Preparation of polysaccharide-protein conjugates 115 4.6.1 Removal of lipid A from Salmonella typhimurium lipopolysaccharide 115 4.6.2 Conjugation of stLFPS with 1,6-hexanediamine via decarboxylative amidation of KDO, giving stLFPS-A/NH2 (6) 115 4.6.3 Conjugation of stLFPS-A/NH2 with bis(4-nitrophenyl) adipate, giving stLFPS-A-B/Np (8) 117 4.6.4 Preparation of stLFPS-peptidylthiolate conjugate stLFPS-A-B-K3G5/SCH2PPh2 (10) 118 4.6.5 Preparation of stLFPS-hexanethiolate conjugate stLFPS-A-B-C6/SCH2PPh2 (30) 119 4.6.6 Preparation of stLFPS-flagellin conjugate self-adjuvanting vaccine stLFPS-A-B-K3G5-stFliC (11) 120 4.6.7 Preparation of stLFPS-flagellin conjugate self-adjuvanting vaccine stLFPS-A-B-C6-stFliC (12) 121 4.6.8 Preparation of stLFPS-flagellin conjugate self-adjuvanting vaccine stLFPS-A-B-stFliC (13) 122 4.6.9 Preparation of stLFPS-BSA conjugate stLFPS-A-B-K3G5-BSA (32) 122 4.6.10 Preparation of stLFPS-BSA conjugate stLFPS-A-B-C6-BSA (33) 123 4.6.11 Preparation of stLFPS-BSA conjugate stLFPS-A-B-BSA (34) 124 4.7 Preparation of linker-BSA conjugates 125 4.7.1 Conjugation of N-(6-aminohexyl)-2-nitrobenzenesulfonamide (4) with bis(4-nitrophenyl) adipate (7), giving Ns-A-B/Np linker (36) 125 4.7.2 Preparation of Ns-A-B-peptidylthiolate derivative Ns-A-B-K3G6/SCH2PPh2 (37) 126 4.7.3 Preparation of Ns-A-B-hexanethiolate derivative Ns-A-B-C6/SCH2PPh2 (38) 127 4.7.4 Preparation of linker-BSA conjugate A-B-K3G5-BSA (39) 127 4.7.5 Preparation of linker-BSA conjugate A-B-C6-BSA (40) 128 4.7.6 Preparation of linker-BSA conjugate A-B-BSA (41) 128 4.8 Reassembling of azido modified flagellin monomers to azido-flagella 129 4.9 Dynamic light scattering (DLS) measurements 130 4.10 TEM Imaging 130 4.11 SDS-PAGE and coomassie blue G-250 staining 131 4.12 Circular dichroism measurement 131 4.13 FT-IR analysis 131 4.14 Fast performance liquid chromatography 132 4.15 Protein digestion 132 4.16 Bicinchoninic acid assay 133 4.17 Phenol-sulfuric acid assay 133 4.18 MALDI-TOF-MS measurement 133 4.19 LC-MS/MS analysis 134 4.20 Label-free quantitation 135 4.21 Molecular modeling of paFliC and assignment of azido-modification sites 136 4.22 Evaluation of hTLR5 activity 136 4.23 Evaluation of vaccination efficacy 138 4.23.1 Mice immunization experiment 138 4.23.2 Serum antibody titer 138 4.23.3 Bacterial challenge test 139 4.23.4 Survival Analysis 139 References 141 Appendix I 157 Appendix II 192 Appendix III 220 | |
| dc.language.iso | en | |
| dc.title | 抗鼠傷寒沙門氏菌之去脂多醣-鞭毛蛋白共軛自佐劑疫苗：製備與效果評估 | zh_TW |
| dc.title | Preparation and Evaluation of Lipid-A Free Lipopolysaccharide-Flagellin Conjugate Self-adjuvanting Vaccine against Salmonella typhimurium | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 107-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 陳平,王宗興,張子文,邱政洵,林俊宏 | |
| dc.subject.keyword | 鞭毛,疫苗,佐劑,脂多醣,傷寒沙門氏菌, | zh_TW |
| dc.subject.keyword | Flagellin,vaccine,adjuvant,lipopolysaccharide,Salmonella typhimurium, | en |
| dc.relation.page | 220 | |
| dc.identifier.doi | 10.6342/NTU201900705 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2019-04-15 | |
| 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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