凝集素與醣體交互作用與選擇性使得許多生理反應得以順利進行，然而其作用力微弱且為可逆非共價鍵結使得儀器難以偵測，成為研究凝集素與醣體作用之阻礙。幸而凝集素多具有多價性結合能力，使我們能設計具多價性且吻合凝集素構形之骨架增加親和力，除此之外開發具有更高親和力的醣體也是值得嘗試的目標。
　　在本研究第一部份中，針對綠膿桿菌生物膜開發抑制劑。在抗生素濫用情況下，綠膿桿菌已對多種抗生素產生抗藥性，也有多重抗藥性的報導，使情況如此嚴苛的原因之一正是生物膜的形成。綠膿桿菌形成生物膜已知與其凝集素LecA與LecB有關，而感染途徑也需藉由凝集素LecA針對宿主細胞表面半乳糖殘基結合。針對LecA蛋白質構形，我們開發出脯胺酸多肽作為具剛性之多價性骨架，藉由其在水中穩定存在之PPII構形來維持有效距離來針對LecA之相鄰結合位，以此骨架與醣體合成多價醣肽共軛物做為抑制劑，利用與最簡單的醣體共軛進行SPR實驗，得到結合力與選擇性兼具的最佳設計後進行醣配體的設計與篩選。醣體上，有文獻報導許多芳香性半乳糖皆具有提升與LecA親和力可能，而實驗室也進行過微陣列掃描實驗也得到一致性的結果。故在此論文中加入三唑環(triazole)之設計並與芳香環一同修飾在醣體中，再利用SPR方法測量與LecA之解離常數，使我們能夠比較醣體上的不同修飾對於親和力的影響。
　　此外，由於肝細胞表面大量表現特有的凝集素去唾液酸醣蛋白受體(Asialoglycoprotein receptor, ASGPR)，有文獻報導此受體亦大量表現在肝癌細胞表面，藉此受體與N-乙醯半乳胺糖殘基結合所產生的胞吞作用可以將藥物載體準確送入目標細胞內以達到基因藥物作用之目的。所以我們嘗試開發出具芳香性N-乙醯半乳胺糖修飾於奈米粒子表面上並乘載螢光siRNA，藉由Hep3B肝癌細胞攝取實驗檢視修飾後的N-乙醯半乳胺糖的結合能力。

Abstract
Carbohydrate-lectin interaction involved in many biological process and mechanism. However, the weak binding affinity of monovalent carbohydrate ligand and lectin is the difficulty to exploit carbohydrate for lectin research. In addition to exploiting multivalent interaction, developing high affinity monovalent carbohydrate derivatives is also a solution to overcome the difficulty.
Over the past decades, antibiotics were commonly used and caused P. aeruginosa rapidly develop resistance during the course of treating an infection. The ability of infection and biofilm formation of P. aeruginosa were mainly caused by LecA to specifically bind to galactose residue of cell surface. Resistance of P. aeruginosa is partly due to its biofilm formation , LecA is a promising target for resistance.
As antibiotic, we developed multivalent scaffold by using polyproline for its PPII structure to maintain the effective distance. We designed and synthesized aromatic galactoside conjugated polyproline material as multivalent ligand binding to neighboring binding site of LecA. By conjugation with simplest galactoside, we knew the best avidity and high selective design. With the result, so we can go further to explore the binding force of structural modification on galactose. In galactoside-synthesis part, it was reported that the aromatic galactoside have higher affinity to LecA than galactose, and so did the triazole galactoside. Given that, we synthesized kinds of the combined aromatic and triazolyl galactoside as ligand to understand the relationship between the aromatic and triazolyl structure and the affinity.
Furthermore, asiaglycoprotein receptor (ASGPR) is an endocytotic cell surface lectin expressed by hepatocyte specifically, that recognized galactoside and GalNAc residue of asiaglycoprotein. So we synthesized the aromatic GalNAc as ligand and conjugated to nanoparticle carrier to test the uptake ability. With modifications on the surface of nanoparticle carrier, the fluorescent siRNA were used as cargo to test the uptake ability of the human hepatoma Hep3B cell line. We found that modified nanoparticles were elevated the ability of uptake by Hep3B and the aromatic part might be an important core during the process of binding. These result may be helpful to design more future Gal/GalNAc based ligand to enhance drug carrier efficiency.

中文摘要 1
Abstract 3
圖目錄 8
表目錄 10
流程目錄 11
縮寫對照表 12
第一章、緒論 14
1.1.前言 14
1.3.多價性效應 16
1.3.1 多價性效應原理 16
1.3.2多價性效應對於凝集素的研究4 21
1.4. 脯胺酸多肽特性與應用 23
1.4.1. 脯胺酸多肽結構與特性 23
1.4.2. 脯胺酸多肽在生物研究上的應用 24
1.5綠膿桿菌凝集素抑制劑 25
1.5.1綠膿桿菌對人類的危害 25
1.5.2綠膿桿菌生物膜的形成與抗藥性機制20 26
1.5.3 綠膿桿菌可溶性凝集素I(PA-IL)的結構與特性 27
1.5.4 LecA抑制劑作為抗綠膿桿菌相關研究 29
1.5.5 具距離調控效果之抑制劑相關研究 31
1.6.表面電漿共振式生物分子感測器(SPR)測定kd 34
1.7 醣脂質對藥物載體奈米粒子的選擇性研究 36
1.7.1 RNAi 藥物以及肝相關疾病相關研究 36
1.7.2 RNAi 藥物運輸奈米粒子載體種類與性質50 37
1.7.3 藥物運送奈米粒子材料對於肝病的研究 40
1.7.4 ASGPR 結構以及胞吞機制 41
1.7.5 醣分子配體對於ASGPR親和力研究 43
1.8 研究動機 44
2.1 LecA配體合成 46
2.1.1 CuAAC 46
2.1.2 具疊氮之半乳糖苷之合成 47
2.2特定間距之二價醣肽合成 53
2.2.1醣肽材料合成之策略 53
2.2.2具炔基脯胺酸構築單元合成 54
2.2.3多肽固相合成脯胺酸多肽骨架 55
2.2.4疊氮-炔類的3+2環化加成 59
2.2.5圓二色光譜結構分析 61
2.3 N-乙醯半乳糖衍生物修飾奈米藥物載體表面對於肝細胞之研究 66
2.3.1醣修飾脂質材料合成之策略 66
2.3.2 N-乙醯半乳胺糖之合成 67
2.3.3具丙炔基之N-乙醯半乳糖苷之合成 68
2.3.4 N-乙醯半乳糖胺糖苷接合脂鰚化合物之合成 71
2.3.5肝細胞對於奈米粒子攝入實驗 72
2.3.6.NPs攝入結果與討論 76
2.4. 結論 77
第三章、實驗方法與材料 79
3.1. Materialand methods 79
3.2. Synthetic procedures and characterization 80
第四章、參考文獻 140

1. Matrosovich, M.; Klenk, H.-D., Natural and synthetic sialic acid-containing inhibitors of influenza virus receptor binding. Reviews in Medical Virology 2003, 13 (2), 85-97.
2. Nair, J. K.; Willoughby, J. L. S.; Chan, A.; Charisse, K.; Alam, M. R.; Wang, Q.; Hoekstra, M.; Kandasamy, P.; Kel’in, A. V.; Milstein, S.; Taneja, N.; O’Shea, J.; Shaikh, S.; Zhang, L.; van der Sluis, R. J.; Jung, M. E.; Akinc, A.; Hutabarat, R.; Kuchimanchi, S.; Fitzgerald, K.; Zimmermann, T.; van Berkel, T. J. C.; Maier, M. A.; Rajeev, K. G.; Manoharan, M., Multivalent N-Acetylgalactosamine-Conjugated siRNA Localizes in Hepatocytes and Elicits Robust RNAi-Mediated Gene Silencing. Journal of the American Chemical Society 2014, 136 (49), 16958-16961.
3. Furukawa, K.; Mattes, M. J.; Lloyd, K. O., A1 and A2 erythrocytes can be distinguished by reagents that do not detect structural differences between the two cell types. The Journal of Immunology 1985, 135 (6), 4090-4094.
4. Mammen, M.; Choi, S.-K.; Whitesides, G. M., Polyvalent Interactions in Biological Systems: Implications for Design and Use of Multivalent Ligands and Inhibitors. Angewandte Chemie International Edition 1998, (37), 2754 - 2794.
5. Cecioni, S.; Imberty, A.; Vidal, S., Glycomimetics versus Multivalent Glycoconjugates for the Design of High Affinity Lectin Ligands. Chemical Reviews 2015, 115 (1), 525-561.
6. Dam, T. K.; Gerken, T. A.; Brewer, C. F., Thermodynamics of Multivalent Carbohydrate−Lectin Cross-Linking Interactions: Importance of Entropy in the Bind and Jump Mechanism. Biochemistry 2009, 48 (18), 3822-3827.
7. Lis, H.; Sharon, N., Lectins:  Carbohydrate-Specific Proteins That Mediate Cellular Recognition. Chemical Reviews 1998, 98 (2), 637-674.
8. Rodriguez, M. C.; Yegorova, S.; Pitteloud, J.-P.; Chavaroche, A. E.; André, S.; Ardá, A.; Minond, D.; Jiménez-Barbero, J.; Gabius, H.-J.; Cudic, M., Thermodynamic Switch in Binding of Adhesion/Growth Regulatory Human Galectin-3 to Tumor-Associated TF Antigen (CD176) and MUC1 Glycopeptides. Biochemistry 2015, 54 (29), 4462-4474.
9. He, X.; Liu, F.; Liu, L.; Duan, T.; Zhang, H.; Wang, Z., Lectin-Conjugated Fe2O3@Au Core@Shell Nanoparticles as Dual Mode Contrast Agents for in Vivo Detection of Tumor. Molecular Pharmaceutics 2014, 11 (3), 738-745.
10. Mikaelyan, M. V.; Poghosyan, G. G.; Hendrickson, O. D.; Dzantiev, B. B.; Gasparyan, V. K., Wheat germ agglutinin and Lens culinaris agglutinin sensitized anisotropic silver nanoparticles in detection of bacteria: A simple photometric assay. Analytica Chimica Acta 2017, 981, 80-85.
11. Richard, E.; Pifferi, C.; Fiore, M.; Samain, E.; Le Gouëllec, A.; Fort, S.; Renaudet, O.; Priem, B., Chemobacterial Synthesis of a Sialyl-Tn Cyclopeptide Vaccine Candidate. ChemBioChem 2017, 18 (17), 1730-1734.
12. Daskhan, G. C.; Berthet, N.; Thomas, B.; Fiore, M.; Renaudet, O., Multivalent glycocyclopeptides: toward nano-sized glycostructures. Carbohydrate Research 2015, 405, 13-22.
13. Galan, M. C.; Dumy, P.; Renaudet, O., Multivalent glyco(cyclo)peptides. Chemical Society Reviews 2013, 42 (11), 4599-4612.
14. Pujol, A. M.; Cuillel, M.; Renaudet, O.; Lebrun, C.; Charbonnier, P.; Cassio, D.; Gateau, C.; Dumy, P.; Mintz, E.; Delangle, P., Hepatocyte Targeting and Intracellular Copper Chelation by a Thiol-Containing Glycocyclopeptide. Journal of the American Chemical Society 2011, 133 (2), 286-296.
15. Wilhelm, P.; Lewandowski, B.; Trapp, N.; Wennemers, H., A Crystal Structure of an Oligoproline PPII-Helix, at Last. Journal of the American Chemical Society 2014, 136 (45), 15829-15832.
16. Beane, G.; Boldt, K.; Kirkwood, N.; Mulvaney, P., Energy Transfer between Quantum Dots and Conjugated Dye Molecules. The Journal of Physical Chemistry C 2014, 118 (31), 18079-18086.
17. Kroll, C.; Mansi, R.; Braun, F.; Dobitz, S.; Maecke, H. R.; Wennemers, H., Hybrid Bombesin Analogues: Combining an Agonist and an Antagonist in Defined Distances for Optimized Tumor Targeting. Journal of the American Chemical Society 2013, 135 (45), 16793-16796.
18. Blanchard, B.; Nurisso, A.; Hollville, E.; Tétaud, C.; Wiels, J.; Pokorná, M.; Wimmerová, M.; Varrot, A.; Imberty, A., Structural Basis of the Preferential Binding for Globo-Series Glycosphingolipids Displayed by Pseudomonas aeruginosa Lectin I. Journal of Molecular Biology 2008, 383 (4), 837-853.
19. Diggle, S. P.; Stacey, R. E.; Dodd, C.; Cámara, M.; Williams, P.; Winzer, K., The galactophilic lectin, LecA, contributes to biofilm development in Pseudomonas aeruginosa. Environmental Microbiology 2006, 8 (6), 1095-1104.
20. Costerton, J. W.; Stewart, P. S.; Greenberg, E. P., Bacterial Biofilms: A Common Cause of Persistent Infections. Science 1999, 284 (5418), 1318.
21. Stewart, P. S., Theoretical aspects of antibiotic diffusion into microbial biofilms. Antimicrobial Agents and Chemotherapy 1996, 40 (11), 2517-2522.
22. Xu, K. D.; Stewart, P. S.; Xia, F.; Huang, C.-T.; McFeters, G. A., Spatial Physiological Heterogeneity in Pseudomonas aeruginosa Biofilm Is Determined by Oxygen Availability. Applied and Environmental Microbiology 1998, 64 (10), 4035-4039.
23. Avichezer, D.; Katcoff, D. J.; Garber, N. C.; Gilboa-Garber, N., Analysis of the amino acid sequence of the Pseudomonas aeruginosa galactophilic PA-I lectin. Journal of Biological Chemistry 1992, 267 (32), 23023-7.
24. Cioci, G.; Mitchell, E. P.; Gautier, C.; Wimmerová, M.; Sudakevitz, D.; Pérez, S.; Gilboa-Garber, N.; Imberty, A., Structural basis of calcium and galactose recognition by the lectin PA-IL of Pseudomonas aeruginosa. FEBS Letters 2003, 555 (2), 297-301.
25. Boukerb, A. M.; Rousset, A.; Galanos, N.; Méar, J.-B.; Thépaut, M.; Grandjean, T.; Gillon, E.; Cecioni, S.; Abderrahmen, C.; Faure, K.; Redelberger, D.; Kipnis, E.; Dessein, R.; Havet, S.; Darblade, B.; Matthews, S. E.; de Bentzmann, S.; Guéry, B.; Cournoyer, B.; Imberty, A.; Vidal, S., Antiadhesive Properties of Glycoclusters against Pseudomonas aeruginosa Lung Infection. Journal of Medicinal Chemistry 2014, 57 (24), 10275-10289.
26. LANNE, B.; CIOPRAGA, J.; BERGSTROM, J.; MOTAS, C.; KARLSSON, K.-A., Binding of the galactose-specific Pseudomonas aeruginosa lectin, PA-I, to glycosphingolipids and other glycoconjugates. Glycoconjugate Journal 1994, (11), 292-298.
27. Eierhoff, T.; Bastian, B.; Thuenauer, R.; Madl, J.; Audfray, A.; Aigal, S.; Juillot, S.; Rydell, G. E.; Müller, S.; de Bentzmann, S.; Imberty, A.; Fleck, C.; Römer, W., A lipid zipper triggers bacterial invasion. Proceedings of the National Academy of Sciences 2014, 111 (35), 12895-12900.
28. Bucior, I.; Abbott, J.; Song, Y.; Matthay, M. A.; Engel, J. N., Sugar administration is an effective adjunctive therapy in the treatment of Pseudomonas aeruginosa pneumonia. American Journal of Physiology - Lung Cellular and Molecular Physiology 2013, 305 (5), L352-L363.
29. Hauber, H.-P.; Schulz, M.; Pforte, A.; Mack, D.; Zabel, P.; Schumacher, U., Inhalation with Fucose and Galactose for Treatment of Pseudomonas Aeruginosa in Cystic Fibrosis Patients. International Journal of Medical Sciences 2008, 5 (6), 371-376.
30. de Lonlay, P.; Seta, N., The clinical spectrum of phosphomannose isomerase deficiency, with an evaluation of mannose treatment for CDG-Ib. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2009, 1792 (9), 841-843.
31. Bergmann, M.; Michaud, G.; Visini, R.; Jin, X.; Gillon, E.; Stocker, A.; Imberty, A.; Darbre, T.; Reymond, J.-L., Multivalency effects on Pseudomonas aeruginosa biofilm inhibition and dispersal by glycopeptide dendrimers targeting lectin LecA. Organic & Biomolecular Chemistry 2016, 14 (1), 138-148.
32. Kottari, N.; Chabre, Y. M.; Shiao, T. C.; Rej, R.; Roy, R., Efficient and accelerated growth of multifunctional dendrimers using orthogonal thiol-ene and SN2 reactions. Chemical Communications 2014, 50 (16), 1983-1985.
33. Pertici, F.; Pieters, R. J., Potent divalent inhibitors with rigid glucose click spacers for Pseudomonas aeruginosa lectin LecA. Chemical Communications 2012, 48 (33), 4008-4010.
34. Wittmann, V.; Pieters, R. J., Bridging lectin binding sites by multivalent carbohydrates. Chemical Society Reviews 2013, 42 (10), 4492-4503.
35. Kitov, P. I.; Sadowska, J. M.; Mulvey, G.; Armstrong, G. D.; Ling, H.; Pannu, N. S.; Read, R. J.; Bundle, D. R., Shiga-like toxins are neutralized by tailored multivalent carbohydrate ligands. Nature 2000, 403 (6770), 669-672.
36. Pertici, F.; de Mol, N. J.; Kemmink, J.; Pieters, R. J., Optimizing Divalent Inhibitors of Pseudomonas aeruginosa Lectin LecA by Using A Rigid Spacer. Chemistry – A European Journal 2013, 19 (50), 16923-16927.
37. Novoa, A.; Eierhoff, T.; Topin, J.; Varrot, A.; Barluenga, S.; Imberty, A.; Römer, W.; Winssinger, N., A LecA Ligand Identified from a Galactoside-Conjugate Array Inhibits Host Cell Invasion by Pseudomonas aeruginosa. Angewandte Chemie International Edition 2014, 53 (34), 8885-8889.
38. Kadam, R. U.; Garg, D.; Schwartz, J.; Visini, R.; Sattler, M.; Stocker, A.; Darbre, T.; Reymond, J.-L., CH−π “T-Shape” Interaction with Histidine Explains Binding of Aromatic Galactosides to Pseudomonas aeruginosa Lectin LecA. ACS Chemical Biology 2013, 8 (9), 1925-1930.
39. Wood, R. W., XLII. On a remarkable case of uneven distribution of light in a diffraction grating spectrum. Philosophical Magazine 1902, 4 (21), 396-402.
40. Fano, U., The Theory of Anomalous Diffraction Gratings and of Quasi-Stationary Waves on Metallic Surfaces (Sommerfeld’s Waves). Journal of the Optical Society of America 1941, 31 (3), 213-222.
41. Hessel, A.; Oliner, A. A., A New Theory of Wood’s Anomalies on Optical Gratings. Applied Optics 1965, 4 (10), 1275-1297.
42. Weinberger, S. R.; Morris, T. S.; Pawlak, M., Recent trends in protein biochip technology. Pharmacogenomics 2000, 1 (4), 395-416.
43. Vos; al., T. e., Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: A systematic analysis for the Global Burden of Disease Study 2013. The Lancet 2015, 385 (9963), 117-171.
44. Ocama, P.; Opio, C. K.; Lee, W. M., Hepatitis B virus infection: Current status. The American Journal of Medicine 2005, 118 (12), 1413.e15-1413.e22.
45. Poelstra, K.; Prakash, J.; Beljaars, L., Drug targeting to the diseased liver. Journal of Controlled Release 2012, 161 (2), 188-197.
46. Dalmay, T.; Hamilton, A.; Rudd, S.; Angell, S.; Baulcombe, D. C., An RNA-Dependent RNA Polymerase Gene in Arabidopsis Is Required for Posttranscriptional Gene Silencing Mediated by a Transgene but Not by a Virus. Cell 2000, 101 (5), 543-553.
47. Oh, Y.-K.; Park, T. G., siRNA delivery systems for cancer treatment. Advanced Drug Delivery Reviews 2009, 61 (10), 850-862.
48. Song, E.; Lee, S.-K.; Wang, J.; Ince, N.; Ouyang, N.; Min, J.; Chen, J.; Shankar, P.; Lieberman, J., RNA interference targeting Fas protects mice from fulminant hepatitis. Nat Med 2003, 9 (3), 347-351.
49. Coelho , T.; Adams , D.; Silva , A.; Lozeron , P.; Hawkins , P. N.; Mant , T.; Perez , J.; Chiesa , J.; Warrington , S.; Tranter , E.; Munisamy , M.; Falzone , R.; Harrop , J.; Cehelsky , J.; Bettencourt , B. R.; Geissler , M.; Butler , J. S.; Sehgal , A.; Meyers , R. E.; Chen , Q.; Borland , T.; Hutabarat , R. M.; Clausen , V. A.; Alvarez , R.; Fitzgerald , K.; Gamba-Vitalo , C.; Nochur , S. V.; Vaishnaw , A. K.; Sah , D. W. Y.; Gollob , J. A.; Suhr , O. B., Safety and Efficacy of RNAi Therapy for Transthyretin Amyloidosis. New England Journal of Medicine 2013, 369 (9), 819-829.
50. Chen, Y.; Gao, D. Y.; Huang, L., In vivo delivery of miRNAs for cancer therapy: Challenges and strategies. Advanced Drug Delivery Reviews 2015, 81, 128-141.
51. van Vlerken, L. E.; Vyas, T. K.; Amiji, M. M., Poly(ethylene glycol)-modified Nanocarriers for Tumor-targeted and Intracellular Delivery. Pharmaceutical Research 2007, 24 (8), 1405-1414.
52. PANYAM, J.; ZHOU, W.-Z.; PRABHA, S.; SAHOO, S. K.; LABHASETWAR, V., Rapid endo-lysosomal escape of poly(dl-lactide-co-glycolide) nanoparticles: implications for drug and gene delivery. The FASEB Journal 2002, 16 (10), 1217-1226.
53. Hsu, S.-h.; Yu, B.; Wang, X.; Lu, Y.; Schmidt, C. R.; Lee, R. J.; Lee, L. J.; Jacob, S. T.; Ghoshal, K., Cationic Lipid Nanoparticles for Therapeutic Delivery of siRNA and miRNA to Murine Liver Tumor. Nanomedicine : nanotechnology, biology, and medicine 2013, 9 (8), 10.1016/j.nano.2013.05.007.
54. Wu, Y.; Crawford, M.; Yu, B.; Mao, Y.; Nana-Sinkam, S. P.; Lee, L. J., MicroRNA Delivery by Cationic Lipoplexes for Lung Cancer Therapy. Molecular Pharmaceutics 2011, 8 (4), 1381-1389.
55. Pecot, C. V.; Calin, G. A.; Coleman, R. L.; Lopez-Berestein, G.; Sood, A. K., RNA interference in the clinic: challenges and future directions. Nature Reviews Cancer 2011, 11 (1), 59-67.
56. Chen, Y.; Zhu, X.; Zhang, X.; Liu, B.; Huang, L., Nanoparticles Modified With Tumor-targeting scFv Deliver siRNA and miRNA for Cancer Therapy. Molecular Therapy 18 (9), 1650-1656.
57. Li, J.; Yang, Y.; Huang, L., Calcium Phosphate Nanoparticles with an Asymmetric Lipid Bilayer Coating for siRNA Delivery to the Tumor. Journal of Controlled Release 2012, 158 (1), 108-114.
58. Clark, G. F.; Schust, D. J., Manifestations of immune tolerance in the human female reproductive tract. Frontiers in Immunology 2013, 4, 26.
59. Tozawa, R.-i.; Ishibashi, S.; Osuga, J.-i.; Yamamoto, K.; Yagyu, H.; Ohashi, K.; Tamura, Y.; Yahagi, N.; Iizuka, Y.; Okazaki, H.; Harada, K.; Gotoda, T.; Shimano, H.; Kimura, S.; Nagai, R.; Yamada, N., Asialoglycoprotein Receptor Deficiency in Mice Lacking the Major Receptor Subunit: ITS OBLIGATE REQUIREMENT FOR THE STABLE EXPRESSION OF OLIGOMERIC RECEPTOR. Journal of Biological Chemistry 2001, 276 (16), 12624-12628.
60. Grewal, P. K.; Uchiyama, S.; Ditto, D.; Varki, N.; Le, D. T.; Nizet, V.; Marth, J. D., The Ashwell receptor mitigates the lethal coagulopathy of sepsis. Nature medicine 2008, 14 (6), 648-655.
61. Hilgard, P.; Schreiter, T.; Stockert, R. J.; Gerken, G.; Treichel, U., Asialoglycoprotein receptor facilitates hemolysis in patients with alcoholic liver cirrhosis. Hepatology 2004, 39 (5), 1398-1407.
62. Weigel, P. H.; Yik, J. H. N., Glycans as endocytosis signals: the cases of the asialoglycoprotein and hyaluronan/chondroitin sulfate receptors. Biochimica et Biophysica Acta (BBA) - General Subjects 2002, 1572 (2), 341-363.
63. Grozovsky, R.; Begonja, A. J.; Liu, K.; Visner, G.; Hartwig, J. H.; Falet, H.; Hoffmeister, K. M., The Ashwell-Morell receptor regulates hepatic thrombopoietin production via JAK2-STAT3 signaling. Nat Med 2015, 21 (1), 47-54.
64. Khorev, O.; Stokmaier, D.; Schwardt, O.; Cutting, B.; Ernst, B., Trivalent, Gal/GalNAc-containing ligands designed for the asialoglycoprotein receptor. Bioorganic & Medicinal Chemistry 2008, 16 (9), 5216-5231.
65. Meier, M.; Bider, M. D.; Malashkevich, V. N.; Spiess, M.; Burkhard, P., Crystal Structure of the Carbohydrate Recognition Domain of the H1 Subunit of the Asialoglycoprotein Receptor. Journal of Molecular Biology 2000, 300 (4), 857-865.
66. Dalton, S. R.; Wiegert, R. L.; Casey, C. A., Receptor-mediated endocytosis by the asialoglycoprotein receptor: effect of ethanol administration on endosomal distribution of receptor and ligand. Liver International 2003, 23 (6), 484-491.
67. Bareford, L. M.; Swaan, P. W., ENDOCYTIC MECHANISMS FOR TARGETED DRUG DELIVERY. Advanced drug delivery reviews 2007, 59 (8), 748-758.
68. Plank, C.; Zatloukal, K.; Cotten, M.; Mechtler, K.; Wagner, E., Gene transfer into hepatocytes using asialoglycoprotein receptor mediated endocytosis of DNA complexed with an artificial tetra-antennary galactose ligand. Bioconjugate Chemistry 1992, 3 (6), 533-539.
69. Rensen, P. C. N.; Sliedregt, L. A. J. M.; Ferns, M.; Kieviet, E.; van Rossenberg, S. M. W.; van Leeuwen, S. H.; van Berkel, T. J. C.; Biessen, E. A. L., Determination of the Upper Size Limit for Uptake and Processing of Ligands by the Asialoglycoprotein Receptor on Hepatocytesin Vitro and in Vivo. Journal of Biological Chemistry 2001, 276 (40), 37577-37584.
70. Worrell, B. T.; Malik, J. A.; Fokin, V. V., Direct Evidence of a Dinuclear Copper Intermediate in Cu(I)-Catalyzed Azide-Alkyne Cycloadditions. Science 2013, 340 (6131), 457.
71. Ligeour, C.; Dupin, L.; Marra, A.; Vergoten, G.; Meyer, A.; Dondoni, A.; Souteyrand, E.; Vasseur, J.-J.; Chevolot, Y.; Morvan, F., Synthesis of Galactoclusters by Metal-Free Thiol “Click Chemistry” and Their Binding Affinities for Pseudomonas aeruginosa Lectin LecA. European Journal of Organic Chemistry 2014, 2014 (34), 7621-7630.
72. Merrifield, R. B., Solid Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide. Journal of the American Chemical Society 1963, 85 (14), 2149-2154.
73. Mamidyala, S. K.; Dutta, S.; Chrunyk, B. A.; Préville, C.; Wang, H.; Withka, J. M.; McColl, A.; Subashi, T. A.; Hawrylik, S. J.; Griffor, M. C.; Kim, S.; Pfefferkorn, J. A.; Price, D. A.; Menhaji-Klotz, E.; Mascitti, V.; Finn, M. G., Glycomimetic Ligands for the Human Asialoglycoprotein Receptor. Journal of the American Chemical Society 2012, 134 (4), 1978-1981.
74. Chen, H.; Xian, T.; Zhang, W.; Si, W.; Luo, X.; Zhang, B.; Zhang, M.; Wang, Z.; Zhang, J., An efficient method for the synthesis of pyranoid glycals. Carbohydrate Research 2016, 431, 42-46.
75. Cao, S.; Meunier, S. J.; Andersson, F. O.; Letellier, M.; Roy, R., Mild stereoselective syntheses of thioglycosides under PTC conditions and their use as active and latent glycosyl donors. Tetrahedron: Asymmetry 1994, 5 (11), 2303-2312.
76. Srinivasan, M.; Sankararaman, S.; Hopf, H.; Dix, I.; Jones, P. G., Syntheses and Structures of Isomeric [6.6]- and [8.8]Cyclophanes with 1,4-Dioxabut-2-yne and 1,6-Dioxahexa-2,4-diyne Bridges. The Journal of Organic Chemistry 2001, 66 (12), 4299-4303.
77. Kao, H.-W.; Chen, C.-L.; Chang, W.-Y.; Chen, J.-T.; Lin, W.-J.; Liu, R.-S.; Wang, H.-E., 18F-FBHGal for asialoglycoprotein receptor imaging in a hepatic fibrosis mouse model. Bioorganic & Medicinal Chemistry 2013, 21 (4), 912-921.
78. Srivastava, A.; Loganathan, D., Synthesis of guanidino sugar conjugates as GlcβArg analogs. Glycoconjugate Journal 2013, 30 (8), 769-780.
79. Hennen, W. J.; Sweers, H. M.; Wang, Y. F.; Wong, C. H., Enzymes in carbohydrate synthesis. Lipase-catalyzed selective acylation and deacylation of furanose and pyranose derivatives. The Journal of Organic Chemistry 1988, 53 (21), 4939-4945.
80. Cheng, H.; Cao, X.; Xian, M.; Fang, L.; Cai, T. B.; Ji, J. J.; Tunac, J. B.; Sun, D.; Wang, P. G., Synthesis and Enzyme-Specific Activation of Carbohydrate−Geldanamycin Conjugates with Potent Anticancer Activity. Journal of Medicinal Chemistry 2005, 48 (2), 645-652.
81. Mihali, V.; Foschi, F.; Penso, M.; Pozzi, G., Chemoselective Synthesis of N-Protected Alkoxyprolines under Specific Solvation Conditions. European Journal of Organic Chemistry 2014, 2014 (24), 5351-5355.
82. Northfield, S. E.; Mountford, S. J.; Wielens, J.; Liu, M.; Zhang, L.; Herzog, H.; Holliday, N. D.; Scanlon, M. J.; Parker, M. W.; Chalmers, D. K.; Thompson, P. E., Propargyloxyproline Regio- and Stereoisomers for Click-Conjugation of Peptides: Synthesis and Application in Linear and Cyclic Peptides. Australian Journal of Chemistry 2015, 68 (9), 1365-1372.
83. Percec, V.; Leowanawat, P.; Sun, H.-J.; Kulikov, O.; Nusbaum, C. D.; Tran, T. M.; Bertin, A.; Wilson, D. A.; Peterca, M.; Zhang, S.; Kamat, N. P.; Vargo, K.; Moock, D.; Johnston, E. D.; Hammer, D. A.; Pochan, D. J.; Chen, Y.; Chabre, Y. M.; Shiao, T. C.; Bergeron-Brlek, M.; André, S.; Roy, R.; Gabius, H.-J.; Heiney, P. A., Modular Synthesis of Amphiphilic Janus Glycodendrimers and Their Self-Assembly into Glycodendrimersomes and Other Complex Architectures with Bioactivity to Biomedically Relevant Lectins. Journal of the American Chemical Society 2013, 135 (24), 9055-9077.
84. García-Viñuales, S.; Delso, I.; Merino, P.; Tejero, T., Stereoselective Ethynylation and Propargylation of Chiral Cyclic Nitrones: Application to the Synthesis of Glycomimetics. 2016.
85. Norberg, O.; Deng, L.; Aastrup, T.; Yan, M.; Ramström, O., Photo-Click Immobilization on Quartz Crystal Microbalance Sensors for Selective Carbohydrate−Protein Interaction Analyses. Analytical Chemistry 2011, 83 (3), 1000-1007.
86. Ueda, M.; Yang, G.; Ishimaru, Y.; Itabashi, T.; Tamura, S.; Kiyota, H.; Kuwahara, S.; Inomata, S.; Shoji, M.; Sugai, T., Hybrid stereoisomers of a compact molecular probe based on a jasmonic acid glucoside: Syntheses and biological evaluations. Bioorganic & Medicinal Chemistry 2012, 20 (19), 5832-5843.
87. Dhande, Y. K.; Wagh, B. S.; Hall, B. C.; Sprouse, D.; Hackett, P. B.; Reineke, T. M., N-Acetylgalactosamine Block-co-Polycations Form Stable Polyplexes with Plasmids and Promote Liver-Targeted Delivery. Biomacromolecules 2016, 17 (3), 830-840.
88. Thomas, B.; Pifferi, C.; Daskhan, G. C.; Fiore, M.; Berthet, N.; Renaudet, O., Divergent and convergent synthesis of GalNAc-conjugated dendrimers using dual orthogonal ligations. Organic & Biomolecular Chemistry 2015, 13 (47), 11529-11538.