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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78861Full metadata record
| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 梁碧惠 | zh_TW |
| dc.contributor.advisor | Pi-Hui Liang | en |
| dc.contributor.author | 賴彥勳 | zh_TW |
| dc.contributor.author | Yen-Hsun Lai | en |
| dc.date.accessioned | 2021-07-11T15:24:48Z | - |
| dc.date.available | 2024-08-16 | - |
| dc.date.copyright | 2019-03-11 | - |
| dc.date.issued | 2019 | - |
| dc.date.submitted | 2002-01-01 | - |
| dc.identifier.citation | 1. Leroux-Roels, G., Unmet needs in modern vaccinology: adjuvants to improve the immune response. Vaccine 2010, 28 Suppl 3, C25-36.
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F., Fusion protein vaccine by domains of bacterial exotoxin linked with a tumor antigen generates potent immunologic responses and antitumor effects. Cancer. Res. 2005, 65, 9089-98. 113. Gerberick, G. F.; Cruse, L. W.; Miller, C. M.; Sikorski, E. E.; Ridder, G. M., Selective modulation of T cell memory markers CD62L and CD44 on murine draining lymph node cells following allergen and irritant treatment. Toxicol. appl. pharmacol. 1997, 146, 1-10. 114. Konishi, N.; Shirahata, T.; Yokoyama, M.; Katsumi, T.; Ito, Y.; Hirata, N.; Nishino, T.; Makino, K.; Sato, N.; Nagai, T.; Kiyohara, H.; Yamada, H.; Kaji, E.; Kobayashi, Y., Synthesis of Bisdesmosidic Oleanolic Acid Saponins via a Glycosylation-Deprotection Sequence under Continuous Microfluidic/Batch Conditions. J. Org. Chem. 2017, 82, 6703-6719. 115. Babouri, R.; Clarion, L.; Rolland, M.; Van der Lee, A.; Kabouche, Z.; Volle, J. N.; Virieux, D.; Pirat, J. L., Synthesis of Oxaphosphinane-Based Pseudodisaccharides. Eur. J. Org. 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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78861 | - |
| dc.description.abstract | 疫苗佐劑為一種免疫調節劑，佐劑結合病原體後能增強免疫系統對病原體的反應，不僅能提高疫苗治療效果亦能減少接種次數。近年來，一種自皂皮樹 (Quillaja saponaria) 樹皮萃取物中得到的皂苷佐劑QS-21被核准用於帶狀皰疹疫苗中，於臨床試驗中QS-21亦被廣泛應用於如癌症、瘧疾和HIV等疫苗。儘管QS-21作為最有潛力的皂苷疫苗佐劑之一，其結構的不穩定性以及潛在的溶血性毒性，於疫苗使用上仍有隱憂，因此為了提供更安全與有效的的疫苗佐劑，本論文以化學合成方式研究皂苷佐劑的結構與活性關聯。
本論文合成了簡化的皂苷核心結構，透過硼試劑B(PhF5)3與適當的保護基修飾，我們成功地將葡萄醣醛酸 (D-glucuronic acid) 鍵結於皂皮酸 (quillaic acid ) 的3號位置；對於皂皮酸28號位置的寡醣鍊的結構活性探討，我們連結了直鍊型三醣以及分支型四醣的結構，三醣結構中的岩藻醣 (D-fucose) 更以阿拉伯醣 (L-arabinose) 取代，以探討其cis-diol對於佐劑活性的影響；此外，刺囊酸 (echinocystic acid) 亦被應用於三萜類骨幹；於碳鍊端的修飾，我們採用了長度不等的脂肪鍊，並以熱安定的醯胺鍵連結。 於小鼠的免疫刺激實驗中，我們使用人類乳突病毒的融合蛋白PEK做為抗原，結合不同碳鍊修飾的皂苷佐劑衍生物做皮下施打，結果發現化合物122 之免疫刺激活性明顯優於脂肪鍊的皂苷衍生物包括GPI-0100，此實驗結果證實皂苷佐劑122能介導強效的細胞免疫反應，適合用於針對細胞內病原體的疫苗製劑。根據此結果，該碳鍊進一步被應用於其餘皂苷衍生物，以測試寡醣鍊變異對於佐劑活性的影響。最後，我們確立了新穎皂苷佐劑的全合成方法，針對碳鍊以及醣鍊做結構修飾，初步免疫實驗結果顯示，這些皂苷佐劑可能成為安全性高且具有細胞免疫偏向之佐劑，可應用於治療性疫苗上。 | zh_TW |
| dc.description.abstract | Vaccine adjuvant is an immune modulator which provides improved protection and safety in vaccination than antigen been used along. Recently, a saponin adjuvant QS-21 has been evidenced for its ability to develop adaptive immune responses for herpes zoster prevention; however, the wider use of saponin QS-21 may be hampered by its dose-limiting toxicity and structural instability.
To address these inconveniences, we synthesized a simplified saponin core structure which contained truncated saccharide unities. The most challenging 3-O-glucuronide was constructed by the catalysis of B(PhF5)3. 28-O linked moieties were diversified to trisaccharide and tetrasaccharide. D-Fucose was replaced by L-Arabinose to probe the potential functions of cis-diol. Echinocystic acid was also applied as quillaic acid triterpene surrogate. In addition, lipophilic alkyl chains were conjugated via a thermal stable amide bond. In a BALB/c mice immunization studies with an antigen PEK, a fusion protein of HPV, we found saponins 122 induced the most promising T-cell mediated cellular immunity. Based on these results, a series of analogues were conjugated at glucuronide to evaluate the structure and activity relationship of these analogues. In conclusion, we provide an accessible and concise approach toward synthesis of saponin adjuvants, and these saponins might become a safer and cellular immunity biased adjuvants for therapeutic vaccines. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T15:24:48Z (GMT). No. of bitstreams: 1 ntu-108-D03423102-1.pdf: 18926239 bytes, checksum: af69afbca5883168059db24763d19390 (MD5) Previous issue date: 2019 | en |
| dc.description.tableofcontents | 口試委員審定書 i
誌謝 ii 摘要 iii Abstract iv List of figures viii List of tables ix List of schemes x Abbreviations xi Structure of protecting groups xiii 1. Introduction 1 1.1. Vaccine adjuvant 1 1.2. Approved vaccine adjuvants 2 1.3. Humoral and cellular immunity 3 1.4. Underdeveloped vaccine adjuvants 5 2. Quillaja saponins 6 2.1. QS-21 and its purified analogues 7 2.2. QS-21 adjuvanted vaccine 9 2.3. Plausible mechanism 10 2.3.1. Surface protein EBI-2 10 2.3.2. Surface receptor DC-SIGN 11 2.3.3. Enhance antigen uptake 11 2.3.4. Lipid body formation 12 2.3.5. Intercellular Schiff-base formation 12 2.3.6. Summary of QS-21 plausible mechanism 13 3. Studies of QS-21 synthesis and SAR 14 3.1. Synthesis of QS-21 and QS-7 14 3.2. GPI-0100 15 3.3. Function of glucuronic acid and aldehyde 16 3.4. Function of Acylation 17 3.4.1. Deacylated Q. saponins 17 3.4.2. Amide bond and linker modifications of QS-21 18 3.5. Function of sugar moieties and aglycon scaffold 19 3.5.1. Truncation of 28-O-linkaged tetrasaccharide 19 3.5.2. Aryl carbon chain and truncation of glucuronide 20 3.6. Aglycon surrogates 21 3.7. Modification of C-17 substituted ester-linkage 22 3.8. Synthesis of QS-21 analogues in GPI-0100 23 3.9. Other saponins with adjuvant activity 24 3.9.1. Quillaja brasiliensis extract 24 3.9.2. Saponins from Chiococca alba 24 3.9.3 Saponins form Spanish saffron Crocus sativus 25 3.10. SAR summary of saponin-based adjuvants 26 4. Motivation 28 5. Result and discussion 29 5.1. Our targets 29 5.2. Retrosynthetic analysis 30 5.3. Oligosaccharide part synthesis 32 5.3.1. Syntheses of building blocks 32 5.3.2. Glycosylation 33 5.3.3. Deprotection of Fmoc. 35 5.3.4. Synthesis of tetrasaccharide 36 5.3.5. Modified synthetic approach to tetrasaccharide 37 5.3.6. Synthesis of trisaccharide donor 38 5.3.7. Modified synthetic approach to trisaccharides 39 5.4. Synthesis of glucuronide 40 5.4.1. Building blocks 41 5.4.2. Koenigs-Knorr glycosylation 42 5.4.3. Schmidt’s glycosylation 43 5.4.4. Glucuronate modification 45 5.4.5. Glucuronidation with pivaloylated donor 45 5.4.6. Glucuronidation with common Lewis acids 47 5.4.7. Glucuronidation of echinocystic ester 48 5.4.8. Glucuronide modification 49 5.5. Conjugation of glucuronide and oligosaccharide parts 50 5.5.1. Conjugation of saponin variants 51 5.5.2. Conjugation of tetrasaccharide and quillaic ester 51 5.6. Terminal aryl-substituted long chain amines synthesis 52 5.7. Global deprotection and amide formation 53 5.8. Immunological evaluation of saponins 115–122 56 5.8.1. E7 specific T-cell activation 56 5.8.2. T-cell activation 57 5.8.3. Memory T-cell stimulation 61 5.8.4. Antibody production assay 63 5.9. Further exploration 64 6. Conclusion 65 7. Experimental section 66 7.1. General procedures 66 7.2. Instrument 66 7.3. Immunological experiments 67 7.3.1. Sample preparation 67 7.3.2. Animal and Vaccinations 67 7.3.3. Splenocytes sample prepare and Flow Cytometry Analysis 67 7.3.4. Flow Cytometric Analysis (Memory T cell) 68 7.3.5. ELISpot 69 7.3.6. ELISA 70 7.4. Synthetic procedure 71 8. References 160 9. Appendices 171 | - |
| dc.language.iso | en | - |
| dc.title | 皂苷疫苗佐劑之合成研究 | zh_TW |
| dc.title | Synthesis of Saponin-Based Vaccine Adjuvants | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 107-1 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.oralexamcommittee | 程正禹;李水盛;陳基旺;忻凌偉;蒙國光 | zh_TW |
| dc.contributor.oralexamcommittee | Chen-Yu Cheng;Shoei-Sheng Lee;Ji-Wang Chern;Ling-Wei Hsin;Kwok-Kong Mong | en |
| dc.subject.keyword | 疫苗佐劑,皂?,QS-21,醣?化反應,細胞免疫活性, | zh_TW |
| dc.subject.keyword | vaccine adjuvant,saponins,QS-21,glycosylation,cellular immunity, | en |
| dc.relation.page | 332 | - |
| dc.identifier.doi | 10.6342/NTU201900035 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2019-01-09 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 藥學研究所 | - |
| dc.date.embargo-lift | 2024-03-11 | - |
| Appears in Collections: | 藥學系 | |
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