蛋白質和蛋白質間的交互作用廣泛地調控龐大的生物機制，包含細胞與細胞間黏合與辨識、細胞間訊息傳遞、病毒或細菌對細胞的傳染、產生免疫反應。然而，闡釋蛋白質和蛋白質間的交互作用的過程是艱難且耗時的，且經常無法顯示清楚的分析結果。尤其又以探討凝集素和醣蛋白間的作用力最為艱鉅，此乃由於醣體與凝集素間作用力為非共價、可逆的鍵結以及微弱親合力。
本論文基於配位基輔助拓印探針的方法，在此簡稱為”LIP”，而發展凝集素探針以用於後續探討凝集素與醣蛋白間之交聯作用；於此研究，先以植物性凝集素Ricinus communis agglutinin 120(RCA120)和B細胞上的跨膜受體cluster of differentiation-22(CD22)應用於第一代凝集素探針之模型蛋白以驗證此策略之可行性，再以recombinant human Siglec-7 Fc chimera protein (Siglec-7-Fc)做為第二代凝集素探針修飾之目標蛋白；LIP的整個架構主要利用amide bond formation化學有效地合成含有多功能基團小分子探針LIP，其中LIP的設計含有五個部分及其功能，以醣體做為配位基將小分子導向凝集素之碳水化合物鍵結位點，再以紫外光激發光敏感基diazirine，於凝集素表面形成共價鍵結，同時啟動光敏斷裂基團之異構化(E-Z isomerization)形成中間體，再以生物素(biotin) 做為純化基團之後，進一步觸發光敏斷裂基團的中間體斷裂，於結合位點上移除醣體和生物素，而將炔基建構於醣結合位點附近以利後續用於生物正交點擊化學反應(Bioorthogonal click chemistry)，以用於合成不同種類之凝集素探針。
本論文以三官能基團探針(含有疊氮基團及光敏感基及生物素)、含疊氮基之環境敏感探針經由Copper(I)-catalyzed Alkyne-Azide Cycloaddition (CuAAC) 反應於炔基化的凝集素上進行修飾以建構凝集素探針，分別應用於凝集素-醣蛋白之交聯反應及免洗滌之HeLa細胞即時監控顯影，最後，我們將修飾炔基化的Siglec-7-Fc與含疊氮基之阿黴素(Doxorubicin)結合做為凝集素藥物，應用於癌細胞抑制實驗中，並藉由MTT assay分析HeLa細胞的活性，結果顯示Siglec-7-Fc-drug可抑制HeLa細胞生長，並以HEK 293細胞做為對照組，證明此凝集素藥物進入細胞之途徑首先為醣蛋白與凝集素之交互作用而進入。
於上述研究過程中，亦發展出以抗癌藥物博來黴素(Bleomycin)之化學結構上的甘露糖部分做為配位基，結合環境敏感小分子所形成之探針以研究醣體與MCF-7膜蛋白之交聯作用，並分別以配位基為甘露糖及半乳醣之環境敏感探針做為對照組，以證明博來黴素經由通過MCF-7膜上之受體進入細胞而非經由小分子擴散(diffusion)進入細胞。

Protein-protein interactions (PPIs) modulate many biological processes. However, elucidation of PPI events is notoriously difficult and time consuming and often yields complex and unclear results. Lectin-glycoprotein interactions are especially difficult to study due to the noncovalent nature of the interactions and inherently low binding affinities of proteins to glycan ligands on glycoproteins. Here, we report a “ligand-assisted imprinting probe” (LIP)-based approach to fabricate protein probes for elucidating protein-glycoprotein interactions. The LIP was designed with dual photoactivatable groups for introduction of a site-specific clickable alkyne handle proximal to the carbohydrate-binding pocket of the lectin, namely, Ricinus communis agglutinin 120, cluster of differentiation-22(CD22) and recombinant human Siglec-7 Fc chimera protein (Siglec-7-Fc). In a proof-of-principle study, alkynylated RCA120 was conjugated with a photoreactive diazirine crosslinker and an environment-sensitive fluorophore by a bioorthogonal click reaction for anchoring the glycoprotein ovalbumin in solution and detecting endogenously expressed glycoproteins on HeLa cells, respectively. An environmental sensor was also site-specifically conjugated on the surface of CD22 near the carbohydrate binding site for no-wash imaging of living HeLa cell. We anticipate that the fabrication of this protein probe will accelerate the discovery of novel PPIs.
Furthermore, we synthesized a second generation LIP for the fabrication of Siglec-7-Fc-drug conjugates via click reaction with azido-doxorubicin and application on the inhibition of HeLa cells viability through the analysis of MTT assay. To validate the Siglec-7-Fc-drug conjugates internalized into HeLa cells through interaction with glycoprotein on the highly expressed sialosides of HeLa cells membrane, HEK 293 cells with low expressed sialosides was used as a control and treated with Siglec-7-Fc-drug conjugates. The result displayed that the glycoprotein on HeLa cells have carbohydrate ligand to bind the carbohydrate binding site of Siglec-7-Fc and doxorubicin can be released in the HeLa cell to further inhibit the viability of cells.
In the application process of lectin probes, we also developed another kind of ligand-directed environmental probes. One of the ligand is the mannose part of bleomycin which is an anti-cancer drug. Other two probes are mannose and galactose as the ligands in separate. We apply these carbohydrate probes to investigate the bleomycin receptor on the membrane of MCF-7. This research result have revealed that there are some feasible receptors interacted with the carbohydrate of bleomycin to internalize into the MCF-7 cells rather than the cellular process by diffusion.

摘要 I
Abstract V
縮寫對照表 VII
目錄 XII
圖目錄 XVII
表目錄 XXIV
第一章 緒論 1
1.1 前言 1
1.2細胞表面之醣體(cell-surface glycans) 3
1.2.1癌細胞表面之唾液酸化醣體 6
1.2.2癌細胞表面之岩藻醣基化醣體 9
1.3 凝集素與醣蛋白作用力之探討 10
1.3.1半乳糖凝集素(Galectins) 13
1.3.2 C型凝集素(C-type lectins) 14
1.3.2.1蓖麻凝集素(Ricinus Communis Agglutinin 120, RCA120) 15
1.3.3唾液酸結合免疫球蛋白型凝集素(Sialic acid-binding immunoglobulin-type lectins, Siglecs) 16
1.3.3.1 分化簇-22 (Cluster of differentiation-22, CD22) 22
1.3.3.2唾液酸免疫球蛋白凝集素-7 (Sialic acid-binding immunoglobulin-type lectins-7, Siglec-7) 25
1.4 研究蛋白質間交互作用之方法探討 27
1.5專一性修飾蛋白質方法之探討 31
1.5.1基因工程法 31
1.5.2化學結合方法 34
1.5.2.1 殘基選擇性標記法 35
1.5.2.2配位基導向標記法 37
1.6 光親合性官能基(Photoaffinity group) 47
1.7斷裂基團(Cleavable linkers) 51
1.8環境敏感基團 59
1.9生物正交化學(Bioorthogonal Reactions) 62
第二章 第一代配位基輔助拓印探針(LIP)修飾凝集素並應用於與醣蛋白間之交互作用研究 64
壹. 研究動機 64
貳. 第一代LIP之構思與設計 65
2.1第一代LIP骨架之構思 65
2.2第一代LIP結構之設計 67
參. 結果與討論 70
3.1建構單元化合物6之合成 70
3.2建構單元化合物8之合成 72
3.3建構單元化合物10之合成 77
3.4建構單元化合物42之合成 78
3.5 LIP 3之合成 79
3.6 LIP 1及化合物48之合成 81
3.7 化合物49之合成 85
3.8化合物53之合成 86
3.9 LIP 3光化學反應之測試 87
3.10 LIP 3及LIP 1於凝集素之修飾流程 90
3.11 LIP 3應用於凝集素RCA120修飾炔基之結果 92
3.12 炔基RCA120之二次修飾 98
3.13 炔基RCA120之二次修飾並以醣晶片進行活性測試 101
3.14 炔基RCA120之二次修飾並應用於凝集素及醣蛋白交互作用之探討 103
3.14.1 探針53建構於RCA120並應用於凝集素-醣蛋白之交聯作用 103
3.14.2 化合物55建構於RCA120並應用於活細胞之凝集素-醣蛋白即時監測 106
3.15 LIP 1及化合物48應用於凝集素CD22-Fc修飾炔基之結果 116
3.16 LIP 1應用於凝集素CD22-Fc修飾與應用 120
肆.結論 125
第三章 以第二代LIP修飾凝集素與醣蛋白間之交互作用之研究 127
壹. 研究動機 127
貳. 第二代LIP之構思與設計 128
2.1第二代LIP骨架之構思 128
2.2第二代LIP結構之設計 131
參. 結果與討論 134
3.1建構單元化合物59之合成路徑A及路徑B 134
3.2建構單元化合物59之合成路徑C 138
3.3化合物82之光反應測試 141
3.4 LIP 58之合成 142
3.5 LIP 57之合成 143
3.6 LIP 58之光反應測試及凝集素修飾流程之設計 146
3.7 LIP 58用於合成炔基RCA120 148
3.8 LIP 57用於合成炔基Siglec-7-Fc 158
3.9 炔基Siglec-7-Fc之藥物修飾 163
3.10 炔基Siglec-7-Fc-Dox之應用 166
肆.結論 174
第四章 探討博萊黴素受體於MCF-7細胞膜之研究 176
壹. 研究動機 176
貳.博萊黴素相關醣體探針構思與設計 177
2.1博萊黴素化合物結構分析 177
2.2. 3-氧-胺甲醯基化甘露糖探針之構思 183
2.3. 3-氧-胺甲醯基化甘露糖探針之設計 184
參. 結果與討論 185
3.1 化合物90及91與MCF-7結合之結果分析 185
3.2 環境敏感醣探針與MCF-7結合之結果分析 188
3.3 光親合性醣探針標記MCF-7之結果分析 194
肆.結論 199
第五章 總結 201
參考文獻 255

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