人類免疫缺乏病毒(HIV)能夠透過其表面糖蛋白gp120的多糖與DC-SIGN和Langerin兩種凝集素結合，其中與DC-SIGN結合後會增強其感染能力，而與Langerin結合後病毒會被細胞所降解，因此許多研究嘗試針對DC-SIGN進行抑制，以減低HIV於體內的感染性。在生物系統中，凝集素與單一醣體的微弱交互作用會以多價交互作用形式增強凝集素與醣體的結合能力，因此本論文運用多價交互作用原理，將數個醣體連接於所開發之聚脯胺酸環肽骨架，並針對DC-SIGN和Langerin進行結合能力之研究。於本論文的第一部分中，我們以具PPII剛性與規律性之聚脯胺酸多肽組裝之聚脯胺酸環肽骨架，並針對其結構及構形進行核磁共振及圓二色性分析。而於第二部分中，我們針對DC-SIGN和Langerin兩種凝集素設計聚脯胺酸環肽骨架，並藉由引入具官能基之脯胺酸衍生物至多肽序列中，以連接高甘露糖醣體而完成聚脯胺酸環醣肽；除此之外，我們利用大腸桿菌表現並純化DC-SIGN和Langerin之細胞外結構域(ECD)供結合能力研究使用。最後我們以表面電漿共振(SPR)對兩種凝集素進行結合能力實驗，以評估此類骨架設計的成效，得到的結果對於將來設計DC-SIGN抑制物有幫助。

Human immunodeficiency virus (HIV) binds to human lectins DC-SIGN and langerin through the glycan on its glycoprotein gp120. Interestingly, viral interaction to langerin leads to virus degradation, but binding to DC-SIGN would enhance T cell infection. Thus, many studies tried to develop selective inhibitor for DC-SIGN. In biological system, the weak affinity between lectin and single glycan would be enhanced through multivalent interaction. In this study, we conjugated multiple glycans to the cyclic polyproline scaffold and examined the interaction toward DC-SIGN and langerin. In the first part of this thesis, we synthesized cyclic polyproline scaffolds and analyzed their structures by NMR and CD. In the second part, we designed glycoconjugates based on cyclic polyproline helix scaffolds for DC-SIGN and langerin. To test the interaction of the glycoconjugates, we expressed DC-SIGN ECD and langerin ECD from E. coli and utilized surface plasmon resonance (SPR) analysis to evaluate the binding avidity. The obtain information are useful for future DC-SIGN inhibitor design.

第一章、 緒論 1
1.1. 前言 1
1.2. 凝集素 3
1.3. 多價交互作用 5
1.3.1. 多價交互作用原理 5
1.3.2. 多價交互作用於凝集素之研究 8
1.3.3. 多價交互作用之骨架 9
1.4. 聚脯胺酸多肽 10
1.4.1. 聚脯胺酸多肽之特性 10
1.4.2. 聚脯胺酸多肽之應用 11
1.5. 人類免疫缺乏病毒 13
1.5.1. 人類免疫缺乏病毒簡介 13
1.5.2. 抗HIV藥物的發展及困境 15
1.6. 樹突細胞與DC-SIGN 16
1.6.1. 樹突細胞簡介 16
1.6.2. DC-SIGN結構解析 17
1.7. 蘭格漢氏細胞與Langerin 18
1.7.1. 蘭格漢氏細胞簡介 18
1.7.2. Langerin結構解析 19
1.8. 研究動機 20
1.9. 實驗設計 21
第二章、 結果與討論 23
2.1. 構築單元之合成 23
2.1.1. 脯胺酸構築單元合成 23
2.1.2. 轉角分子合成 24
2.2. 模型脯胺酸環肽四聚體之合成與分析 25
2.2.1. 聚脯胺酸環肽四聚體合成策略 25
2.2.3.最佳化組裝之CuAAC反應條件 29
2.2.4. 模型脯胺酸環肽四聚體合成 31
2.2.5. 圓二色光譜分析 34
2.2.6. 核磁共振光譜分析 35
2.3. 聚脯胺酸環醣肽寡聚體之合成與分析 36
2.3.1. 聚脯胺酸環肽寡聚體合成 36
2.3.2. 聚脯胺酸環醣肽寡聚體合成 39
2.3.3. 圓二色光譜分析 40
2.4. 蛋白質的表現與純化 41
2.4.1. Langerin ECD (Lg-ECD) 41
2.4.2. DC-SIGN ECD (DC-ECD) 42
2.5. 聚脯胺酸環醣肽寡聚體與凝集素之結合能力 44
2.5.1. 表面電漿共振 44
2.5.2. 多價醣樹狀化合物合成 45
2.5.3. Langerin的結合能力實驗 45
2.5.4. DC-SIGN的結合能力實驗 48
2.5.5. 對於Langerin和DC-SIGN之選擇性比較 50
2.6. 結論 52
第三章、 實驗方法與材料 54
3.1. General Methods for Synthesis and Characterization 54
3.2. Synthesis of Peptide Building Blocks and Connector 55
3.3. Synthesis of Peptide and Glycopeptide Oligomers 65
3.4. Expression and Purification of target Lectins 91
3.5. Synthesis of Glycodendrimers 93
3.6. Surface Plasmon Resonance Assay 94
第四章、 參考資料 96

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