多價性配體–受體交互作用在生物識別和訊號傳遞中扮演不可或缺的角色，由於細胞表面的受體排列可以改變這些結果，且對配體的結合具有空間選擇性，因此控制配體的展示成為操控或選擇性標靶受體的策略之一。
　　在本論文中，我們利用在固相上的模組化組裝反應合成了聚脯胺酸三聚體，並藉由分析其性質，將轉角分子最佳化以提高骨架的穩定性，再以生物共軛反應連接大小不同的醣配體以操縱它們的排列。我們除了使用表面電漿共振技術證明和凝集素結合位排列相符的配體排列方式可以有選擇性的結合外，也證實帶有螢光基團的聚脯胺酸環肽能夠選擇性的標記在肝癌細胞上的去唾液酸醣蛋白受體寡聚體。最後我們將聚脯胺酸環肽連接至PNA·DNA複合物上，預期能以血球凝集抑制試驗或表面電漿共振技術評估其對A型流感病毒的距離–抑制能力關係。
　　由於聚脯胺酸環肽骨架可將配體以多樣化的排列方式展示，且具有高水溶性與生物相容性，因此可用以探測或操控細胞表面受體的排列，以研究其對訊號傳遞與細胞識別的影響，使得此新穎生物分子骨架具有作為奈米藥物的潛力。

　　Multivalent ligand–receptor interactions play essential roles in　biological　recognition and signaling. As the receptor arrangement can　alter the outcome of cell　signaling and also provide spatial　specificity for ligand binding, controlling the ligand　patterns has　become a strategy to manipulate or selectively target protein　receptors.
　　In this dissertation, we have developed modular assembly of　peptides on solid　support to synthesize polyproline tri-helix macrocycles, which were further　characterized to optimize the　connectors design for the scaffold stability. We ligated　various　glycan ligands to different scaffolds and the resulting　glycoconjugates were　tested in surface plasmon resonance assays to　demonstrate the selectivity of the　matching ligand pattern toward　matching binding sites arrangement of lectins. The　fluorescent　glycoconjugates also selectively labeled asialoglycoprotein receptor　oligomer on hepatoma cells which indicates their capability on cell　surface. We further　combined the polyproline-based scaffolds to　PNA·DNA which could be applied to test　the topology–inhibition　relationship of complex to influenza A virus.
　　As the scaffold design allows display ligand in versatile patterns　with aqueous　solublity and biocompatibility, it has become a promising tool to probe the arrangement　of receptors on the cell surface and as nanomedicine to manipulate signaling or cell　recognition.

1. Bornhöfft, K. F.; Goldammer, T.; Rebl, A.; Galuska, S. P. Siglecs: A journey through the evolution of sialic acid-binding immunoglobulin-type lectins. Dev. Comp. Immunol. 2018, 86, 219–231.
2. Büll, C.; den Brok, M. H.; Adema, G. J. Sweet escape: Sialic acids in tumor immune evasion. Biochim. Biophys. Acta, Rev. Cancer 2014, 1846, 238–246.
3. Holgersson, J.; Gustafsson, A.; Breimer, M. E. Characteristics of protein–carbohydrate interactions as a basis for developing novel carbohydrate-based antirejection therapies. Immunol. Cell Biol. 2005, 83, 694–708.
4. Lis, H.; Sharon, N. Lectins: Carbohydrate-specific proteins that mediate cellular recognition. Chem. Rev. 1998, 98, 637–674.
5. Gupta, D.; Bhattacharyya, L.; Fant, J.; Macaluso, F.; Sabesan, S.; Brewer, C. F. Observation of unique cross-linked lattices between multiantennary carbohydrates and soybean lectin. Presence of pseudo-2-fold axes of symmetry in complex type carbohydrates. Biochemistry 1994, 33, 7495–7504.
6. Monsigny, M.; Roche, A.-C.; Sene, C.; Maget-Dana, R.; Delmotte, F. Sugar-lectin interactions: How does wheat-germ agglutinin bind sialoglycoconjugates? Eur. J. Biochem. 1980, 104, 147–153.
7. Vasta, G. R. Galectins as pattern recognition receptors: Structure, function, and evolution. Adv. Exp. Med. Biol. 2012, 946, 21–36.
8. Silva, M.; Videira, P. A.; Sackstein, R. E-selectin ligands in the human mononuclear phagocyte system: Implications for infection, inflammation, and immunotherapy. Front. Immunol. 2018, 8, 1878.
9. Mammen, M.; Choi, S.-K.; Whitesides, G. M. Polyvalent interactions in biological systems: Implications for design and use of multivalent ligands and inhibitors. Angew. Chem. Int. Ed. 1998, 37, 2754–2794.
10. Mammen, M.; Shakhnovich, E. I.; Deutch, J. M.; Whitesides, G. M. Estimating the entropic cost of self-assembly of multiparticle hydrogen-bonded aggregates based on the cyanuric acid·melamine lattice. J. Org. Chem. 1998, 63, 3821–3830.
11. Mammen, M.; Shakhnovich, E. I.; Whitesides, G. M. Using a convenient, quantitative model for torsional entropy to establish qualitative trends for molecular processes that restrict conformational freedom. J. Org. Chem. 1998, 63, 3168–3175.
12. Bujotzek, A.; Shan, M.; Haag, R.; Weber, M. Towards a rational spacer design for bivalent inhibition of estrogen receptor. J. Comput. Aided Mol. Des. 2011, 25, 253–262.
13. Kiessling, L. L.; Gestwicki, J. E.; Strong, L. E. Synthetic multivalent ligands as probes of signal transduction. Angew. Chem. Int. Ed. 2006, 45, 2348–2368.
14. Fasting, C.; Schalley, C. A.; Weber, M.; Seitz, O.; Hecht, S.; Koksch, B.; Dernedde, J.; Graf, C.; Knapp, E.-W.; Haag, R. Multivalency as a chemical organization and action principle. Angew. Chem. Int. Ed. 2012, 51, 10472–10498.
15. Gestwicki, J. E.; Cairo, C. W.; Strong, L. E.; Oetjen, K. A.; Kiessling, L. L. Influencing receptor−ligand binding mechanisms with multivalent ligand architecture. J. Am. Chem. Soc. 2002, 124, 14922–14933.
16. Mammen, M.; Dahmann, G.; Whitesides, G. M. Effective inhibitors of hemagglutination by influenza virus synthesized from polymers having active ester groups. Insight into mechanism of inhibition. J. Med. Chem. 1995, 38, 4179–4190.
17. Jayaraman, N.; Maiti, K.; Naresh, K. Multivalent glycoliposomes and micelles to study carbohydrate–protein and carbohydrate–carbohydrate interactions. Chem. Soc. Rev. 2013, 42, 4640–4656.
18. Appelhans, D.; Klajnert-Maculewicz, B.; Janaszewska, A.; Lazniewska, J.; Voit, B. Dendritic glycopolymers based on dendritic polyamine scaffolds: View on their synthetic approaches, characteristics and potential for biomedical applications. Chem. Soc. Rev. 2015, 44, 3968–3996.
19. Kiessling, L. L.; Grim, J. C. Glycopolymer probes of signal transduction. Chem. Soc. Rev. 2013, 42, 4476–4491.
20. Müller, C.; Despras, G.; Lindhorst, T. K. Organizing multivalency in carbohydrate recognition. Chem. Soc. Rev. 2016, 45, 3275–3302.
21. Marradi, M.; Chiodo, F.; García, I.; Penadés, S. Glyconanoparticles as multifunctional and multimodal carbohydrate systems. Chem. Soc. Rev. 2013, 42, 4728–4745.
22. Unverzagt, C.; André, S.; Seifert, J.; Kojima, S.; Fink, C.; Srikrishna, G.; Freeze, H.; Kayser, K.; Gabius, H.-J. Structure−activity profiles of complex biantennary glycans with core fucosylation and with/without additional α2,3/α2,6 sialylation: Synthesis of neoglycoproteins and their properties in lectin assays, cell binding, and organ uptake. J. Med. Chem. 2002, 45, 478–491.
23. Galan, M. C.; Dumy, P.; Renaudet, O. Multivalent glyco(cyclo)peptides. Chem. Soc. Rev. 2013, 42, 4599–4612.
24. Novoa, A.; Winssinger, N. DNA display of glycoconjugates to emulate oligomeric interactions of glycans. Beilstein J. Org. Chem. 2015, 11, 707–719.
25. Cecioni, S.; Imberty, A.; Vidal, S. Glycomimetics versus multivalent glycoconjugates for the design of high affinity lectin ligands. Chem. Rev. 2015, 115, 525–561.
26. Traub, W.; Shmueli, U. Structure of poly-L-proline I. Nature 1963, 198, 1165–1166.
27. Cowan, P. M.; McGavin, S. Structure of poly-L-proline. Nature 1955, 176, 501–503.
28. Wilhelm, P.; Lewandowski, B.; Trapp, N.; Wennemers, H. A crystal structure of an oligoproline PPII-helix, at last. J. Am. Chem. Soc. 2014, 136, 15829–15832.
29. Naziga, E. B.; Schweizer, F.; Wetmore, S. D. Solvent interactions stabilize the polyproline II conformation of glycosylated oligoprolines. J. Phys. Chem. B 2013, 117, 2671–2681.
30. Schuler, B.; Lipman, E. A.; Steinbach, P. J.; Kumke, M.; Eaton, W. A. Polyproline and the “spectroscopic ruler” revisited with single-molecule fluorescence. Proc. Natl. Acad. Sci. U. S. A. 2005, 102, 2754–2759.
31. 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. J. Am. Chem. Soc. 2013, 135, 16793–16796.
32. Nepal, M.; Thangamani, S.; Seleem, M. N.; Chmielewski, J. Targeting intracellular bacteria with an extended cationic amphiphilic polyproline helix. Org. Biomol. Chem. 2015, 13, 5930–5936.
33. Yoshida, K.; Kawamura, S.-i.; Morita, T.; Kimura, S. Helix triangle: Unique peptide-based molecular architecture. J. Am. Chem. Soc. 2006, 128, 8034–8041.
34. Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. A stepwise Huisgen cycloaddition process: Copper(I)‐catalyzed regioselective “ligation” of azides and terminal alkynes. Angew. Chem. Int. Ed. 2002, 41, 2596–2599.
35. Li, L.; Zhang, Z. Development and applications of the copper-catalyzed azide-alkyne cycloaddition (CuAAC) as a bioorthogonal reaction. Molecules 2016, 21, 1393.
36. 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, 457–460.
37. Cho, D.; Masuoka, K.; Koguchi, K.; Asari, T.; Kawaguchi, D.; Takano, A.; Matsushita, Y. Preparation and characterization of cyclic polystyrenes. Polym. J. 2005, 37, 506–511.
38. Kalia, J.; Raines, R. T. Advances in bioconjugation. Curr. Org. Chem. 2010, 14, 138–147.
39. McKay, Craig S.; Finn, M. G. Click chemistry in complex mixtures: Bioorthogonal bioconjugation. Chem. Biol. 2014, 21, 1075–1101.
40. Dondoni, A.; Massi, A.; Nanni, P.; Roda, A. A new ligation strategy for peptide and protein glycosylation: Photoinduced thiol–ene coupling. Chem. - Eur. J. 2009, 15, 11444–11449.
41. Hoyle, C. E.; Bowman, C. N. Thiol–ene click chemistry. Angew. Chem. Int. Ed. 2010, 49, 1540–1573.
42. Kümin, M.; Sonntag, L.-S.; Wennemers, H. Azidoproline containing helices: Stabilization of the polyproline II structure by a functionalizable group. J. Am. Chem. Soc. 2007, 129, 466–467.
43. Peters, C.; Bacher, M.; Buenemann, C. L.; Kricek, F.; Rondeau, J.-M.; Weigand, K. Conformationally constrained mimics of the membrane-proximal domain of FcεRIα. Chembiochem 2007, 8, 1785–1789.
44. Skirtenko, N.; Richman, M.; Nitzan, Y.; Gedanken, A.; Rahimipour, S. A facile one-pot sonochemical synthesis of surface-coated mannosyl protein microspheres for detection and killing of bacteria. Chem. Commun. 2011, 47, 12277–12279.
45. Kleinert, M.; Röckendorf, N.; Lindhorst, Thisbe K. Glyco‐SAMs as glycocalyx mimetics: Synthesis of L‐fucose‐ and D‐mannose‐terminated building blocks. Eur. J. Org. Chem. 2004, 2004, 3931–3940.
46. Criegee, R. Mechanism of ozonolysis. Angew. Chem. Int. Ed. Engl. 1975, 14, 745–752.
47. 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. Carbohydr. Res. 2016, 431, 42–46.
48. Lemieux, R. U.; Ratcliffe, R. M. The azidonitration of tri-O-acetyl-D-galactal. Can. J. Chem. 1979, 57, 1244–1251.
49. Nyffeler, P. T.; Liang, C.-H.; Koeller, K. M.; Wong, C.-H. The chemistry of amine−azide interconversion: Catalytic diazotransfer and regioselective azide reduction. J. Am. Chem. Soc. 2002, 124, 10773–10778.
50. 溫興荃。聚脯胺酸環肽的合成及其在DC-SIGN 和Langerin 之應用。碩士論文，國立清華大學化學系，新竹市，2018。
51. 黃任陞。以多價醣類共軛物增強醣類與蛋白質之交互作用。碩士論文，國立清華大學化學系，新竹市，2017。
52. Cummings, R. D.; Schnaar, R. L.; Esko, J. D.; Drickamer, K.; Taylor, M. E. Principles of Glycan Recognition. In Essentials of Glycobiology, 3rd ed.; Varki, A.; Cummings, R. D.; Esko, J. D.; Stanley, P.; Hart, G. W.; Aebi, M.; Darvill, A. G.; Kinoshita, T.; Packer, N. H.; Prestegard, J. H.; Schnaar, R. L.; Seeberger, P. H., Eds; Cold Spring Harbor Laboratory Press: New York, 2017; pp 373–385.
53. Engvall, E.; Perlmann, P. Enzyme-linked immunosorbent assay, Elisa. J. Immunol. 1972, 109, 129–135.
54. Liang, P.-H.; Wang, S.-K.; Wong, C.-H. Quantitative analysis of carbohydrate−protein interactions using glycan microarrays: Determination of surface and solution dissociation constants. J. Am. Chem. Soc. 2007, 129, 11177–11184.
55. Burger, M. M. Assays for agglutination with lectins. Methods Enzymol. 1974, 32, 615–621.
56. Sanchez, J.-F.; Lescar, J.; Chazalet, V.; Audfray, A.; Gagnon, J.; Alvarez, R.; Breton, C.; Imberty, A.; Mitchell, E. P. Biochemical and structural analysis of Helix pomatia agglutinin: A hexameric lectin with a novel fold. J. Biol. Chem. 2006, 281, 20171–20180.
57. Dam, T. K.; Brewer, C. F. Multivalent protein–carbohydrate interactions: Isothermal titration microcalorimetry studies. Methods Enzymol. 2004, 379, 107–128.
58. Concepcion, J.; Witte, K.; Wartchow, C.; Choo, S.; Yao, D.; Persson, H.; Wei, J.; Li, P.; Heidecker, B.; Ma, W.; Varma, R.; Zhao, L.-S.; Perillat, D.; Carricato, G.; Recknor, M.; Du, K.; Ho, H.; Ellis, T.; Gamez, J.; Howes, M.; Phi-Wilson, J.; Lockard, S.; Zuk, R.; Tan, H. Label-free detection of biomolecular interactions using BioLayer interferometry for kinetic characterization. Comb. Chem. High Throughput Screening 2009, 12, 791–800.
59. Wienken, C. J.; Baaske, P.; Rothbauer, U.; Braun, D.; Duhr, S. Protein-binding assays in biological liquids using microscale thermophoresis. Nat. Commun. 2010, 1, 100.
60. Yakovleva, M. E.; Safina, G. R.; Danielsson, B. A study of glycoprotein–lectin interactions using quartz crystal microbalance. Anal. Chim. Acta 2010, 668, 80–85.
61. Abdulhalim, I.; Zourob, M.; Lakhtakia, A. Surface plasmon resonance for biosensing: A mini-review. Electromagnetics 2008, 28, 214–242.
62. Duverger, E.; Frison, N.; Roche, A.-C.; Monsigny, M. Carbohydrate-lectin interactions assessed by surface plasmon resonance. Biochimie 2003, 85, 167–179.
63. Cooper, M. A. Optical biosensors in drug discovery. Nat. Rev. Drug Discovery 2002, 1, 515–528.
64. Godula, K.; Bertozzi, C. R. Density variant glycan microarray for evaluating cross-linking of mucin-like glycoconjugates by lectins. J. Am. Chem. Soc. 2012, 134, 15732–15742.
65. Dessen, A.; Gupta, D.; Sabesan, S.; Brewer, C. F.; Sacchettini, J. C. X-ray crystal structure of the soybean agglutinin cross-linked with a biantennary analog of the blood group I carbohydrate antigen. Biochemistry 1995, 34, 4933–4942.
66. Pan, A. C.; Borhani, D. W.; Dror, R. O.; Shaw, D. E. Molecular determinants of drug–receptor binding kinetics. Drug Discovery Today 2013, 18, 667–673.
67. D'Souza, A. A.; Devarajan, P. V. Asialoglycoprotein receptor mediated hepatocyte targeting — Strategies and applications. J. Controlled Release 2015, 203, 126–139.
68. Baenziger, J. U.; Maynard, Y. Human hepatic lectin. Physiochemical properties and specificity. J. Biol. Chem. 1980, 255, 4607–4613.
69. Renz, M.; Daniels, B. R.; Vámosi, G.; Arias, I. M.; Lippincott-Schwartz, J. Plasticity of the asialoglycoprotein receptor deciphered by ensemble FRET imaging and single-molecule counting PALM imaging. Proc. Natl. Acad. Sci. U. S. A. 2012, 109, E2989–E2997.
70. Rice, K. G.; Wu, P.; Brand, L.; Lee, Y. C. Interterminal distance and flexibility of a triantennary glycopeptide as measured by resonance energy transfer. Biochemistry 1991, 30, 6646–6655.
71. Rice, K. G.; Rao, N. B. N.; Lee, Y. C. Large-scale preparation and characterization of N-linked glycopeptides from bovine fetuin. Anal. Biochem. 1990, 184, 249–258.
72. Khorev, O.; Stokmaier, D.; Schwardt, O.; Cutting, B.; Ernst, B. Trivalent, Gal/GalNAc-containing ligands designed for the asialoglycoprotein receptor. Biorg. Med. Chem. 2008, 16, 5216–5231.
73. Cheng, K.; Zhou, Y.; Neelamegham, S. DrawGlycan-SNFG: A robust tool to render glycans and glycopeptides with fragmentation information. Glycobiology 2016, 27, 200–205.
74. Geuze, H. J.; Slot, J. W.; Strous, G. J. A. M.; Lodish, H. F.; Schwartz, A. L. Intracellular site of asialoglycoprotein receptor-ligand uncoupling: Double-label immunoelectron microscopy during receptor-mediated endocytosis. Cell 1983, 32, 277–287.
75. Steirer, L. M.; Park, E. I.; Townsend, R. R.; Baenziger, J. U. The asialoglycoprotein receptor regulates levels of plasma glycoproteins terminating with sialic acid α2,6-galactose. J. Biol. Chem. 2009, 284, 3777–3783.
76. 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. Nat. Med. 2008, 14, 648–655.
77. 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. J. Am. Chem. Soc. 2012, 134, 1978–1981.
78. Huang, X.; Leroux, J.-C.; Castagner, B. Well-defined multivalent ligands for hepatocytes targeting via asialoglycoprotein receptor. Bioconjugate Chem. 2017, 28, 283–295.
79. Sanhueza, C. A.; Baksh, M. M.; Thuma, B.; Roy, M. D.; Dutta, S.; Préville, C.; Chrunyk, B. A.; Beaumont, K.; Dullea, R.; Ammirati, M.; Liu, S.; Gebhard, D.;Finley, J. E.; Salatto, C. T.; King-Ahmad, A.; Stock, I.; Atkinson, K.; Reidich, B.; Lin, W.; Kumar, R.; Tu, M.; Menhaji-Klotz, E.; Price, D. A.; Liras, S.; Finn, M. G.; Mascitti, V. Efficient liver targeting by polyvalent display of a compact ligand for the asialoglycoprotein receptor. J. Am. Chem. Soc. 2017, 139, 3528–3536.
80. Wei, M.; Guo, X.; Tu, L.; Zou, Q.; Li, Q.; Tang, C.; Chen, B.; Xu, Y.; Wu, C. Lactoferrin-modified PEGylated liposomes loaded with doxorubicin for targeting delivery to hepatocellular carcinoma. Int. J. Nanomed. 2015, 10, 5123–5137.
81. Wu, D.-Q.; Lu, B.; Chang, C.; Chen, C.-S.; Wang, T.; Zhang, Y.-Y.; Cheng, S.-X.; Jiang, X.-J.; Zhang, X.-Z.; Zhuo, R.-X. Galactosylated fluorescent labeled micelles as a liver targeting drug carrier. Biomaterials 2009, 30, 1363–1371.
82. Huang, K.-W.; Lai, Y.-T.; Chern, G.-J.; Huang, S.-F.; Tsai, C.-L.; Sung, Y.-C.; Chiang, C.-C.; Hwang, P.-B.; Ho, T.-L.; Huang, R.-L.; Shiue, T.-Y.; Chen, Y.; Wang, S.-K. Galactose derivative-modified nanoparticles for efficient siRNA delivery to hepatocellular carcinoma. Biomacromolecules 2018, 19, 2330–2339.
83. Prakash, T. P.; Yu, J.; Migawa, M. T.; Kinberger, G. A.; Wan, W. B.; Østergaard, M. E.; Carty, R. L.; Vasquez, G.; Low, A.; Chappell, A.; Schmidt, K.; Aghajan, M.; Crosby, J.; Murray, H. M.; Booten, S. L.; Hsiao, J.; Soriano, A.; Machemer, T.; Cauntay, P.; Burel, S. A.; Murray, S. F.; Gaus, H.; Graham, M. J.; Swayze, E. E.; Seth, P. P. Comprehensive structure–activity relationship of triantennary N-acetylgalactosamine conjugated antisense oligonucleotides for targeted delivery to hepatocytes. J. Med. Chem. 2016, 59, 2718–2733.
84. Garbuio, L.; Lewandowski, B.; Wilhelm, P.; Ziegler, L.; Yulikov, M.; Wennemers, H.; Jeschke, G. Shape persistence of polyproline II helical oligoprolines. Chem. - Eur. J. 2015, 21, 10747–10753.
85. Potter, C. W. A history of influenza. J. Appl. Microbiol. 2001, 91, 572–579.
86. Dou, D.; Revol, R.; Östbye, H.; Wang, H.; Daniels, R. Influenza A virus cell entry, replication, virion assembly and movement. Front. Immunol. 2018, 9, 1581.
87. Davies, W. L.; Grunert, R. R.; Haff, R. F.; McGahen, J. W.; Neumayer, E. M.; Paulshock, M.; Watts, J. C.; Wood, T. R.; Hermann, E. C.; Hoffmann, C. E. Antiviral activity of 1-adamantanamine (amantadine). Science 1964, 144, 862–863.
88. Tsunoda, A.; Maassab, H. F.; Cochran, K. W.; Eveland, W. C. Antiviral activity of alpha-methyl-1-adamantanemethylamine hydrochloride. Antimicrob. Agents Chemother. 1965, 5, 553–560.
89. Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H.; Zhang, L.; Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Mendel, D. B.; Tai, C. Y.; Laver, W. G.; Stevens, R. C. Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: Design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity. J. Am. Chem. Soc. 1997, 119, 681–690.
90. Hurt, A. C.; Holien, J. K.; Parker, M. W.; Barr, I. G. Oseltamivir resistance and the H274Y neuraminidase mutation in seasonal, pandemic and highly pathogenic influenza viruses. Drugs 2009, 69, 2523–2531.
91. Steinhauer, D. A. Role of hemagglutinin cleavage for the pathogenicity of influenza virus. Virology 1999, 258, 1–20.
92. Harris, A.; Cardone, G.; Winkler, D. C.; Heymann, J. B.; Brecher, M.; White, J. M.; Steven, A. C. Influenza virus pleiomorphy characterized by cryoelectron tomography. Proc. Natl. Acad. Sci. U. S. A. 2006, 103, 19123–19127.
93. Oka, H.; Onaga, T.; Koyama, T.; Guo, C.-T.; Suzuki, Y.; Esumi, Y.; Hatano, K.; Terunuma, D.; Matsuoka, K. Sialyl α(2→3) lactose clusters using carbosilane dendrimer core scaffolds as influenza hemagglutinin blockers. Bioorg. Med. Chem. Lett. 2008, 18, 4405–4408.
94. Yeh, H.-W.; Lin, T.-S.; Wang, H.-W.; Cheng, H.-W.; Liu, D.-Z.; Liang, P.-H. S-linked sialyloligosaccharides bearing liposomes and micelles as influenza virus inhibitors. Org. Biomol. Chem. 2015, 13, 11518–11528.
95. Lauster, D.; Glanz, M.; Bardua, M.; Ludwig, K.; Hellmund, M.; Hoffmann, U.; Hamann, A.; Böttcher, C.; Haag, R.; Hackenberger, C. P. R.; Herrmann, A. Multivalent peptide–nanoparticle conjugates for influenza-virus inhibition. Angew. Chem. Int. Ed. 2017, 56, 5931–5936.
96. Sigal, G. B.; Mammen, M.; Dahmann, G.; Whitesides, G. M. Polyacrylamides bearing pendant α-sialoside groups strongly inhibit agglutination of erythrocytes by influenza virus: The strong inhibition reflects enhanced binding through cooperative polyvalent interactions. J. Am. Chem. Soc. 1996, 118, 3789–3800.
97. Bandlow, V.; Liese, S.; Lauster, D.; Ludwig, K.; Netz, R. R.; Herrmann, A.; Seitz, O. Spatial screening of hemagglutinin on influenza A virus particles: Sialyl-LacNAc displays on DNA and PEG scaffolds reveal the requirements for bivalency enhanced interactions with weak monovalent binders. J. Am. Chem. Soc. 2017, 139, 16389–16397.
98. Ohta, T.; Miura, N.; Fujitani, N.; Nakajima, F.; Niikura, K.; Sadamoto, R.; Guo, C.-T.; Suzuki, T.; Suzuki, Y.; Monde, K.; Nishimura, S.-I. Glycotentacles: Synthesis of cyclic glycopeptides, toward a tailored blocker of influenza virus hemagglutinin. Angew. Chem. Int. Ed. 2003, 42, 5186–5189.
99. Waldmann, M.; Jirmann, R.; Hoelscher, K.; Wienke, M.; Niemeyer, F. C.; Rehders, D.; Meyer, B. A nanomolar multivalent ligand as entry inhibitor of the hemagglutinin of avian influenza. J. Am. Chem. Soc. 2014, 136, 783–788.
100. Lu, W.; Du, W.; Somovilla, V. J.; Yu, G.; Haksar, D.; de Vries, E.; Boons, G.-J.; deVries, R. P.; de Haan, C. A. M.; Pieters, R. J. Enhanced inhibition of influenza A virus adhesion by di- and trivalent hemagglutinin inhibitors. J. Med. Chem. 2019, 62, 6398–6404.
101. Kiran, P.; Bhatia, S.; Lauster, D.; Aleksić, S.; Fleck, C.; Peric, N.; Maison, W.; Liese, S.; Keller, B. G.; Herrmann, A.; Haag, R. Exploring rigid and flexible core trivalent sialosides for influenza virus inhibition. Chem. - Eur. J. 2018, 24, 19373–19385.
102. Yamabe, M.; Kaihatsu, K.; Ebara, Y. Sialyllactose-modified three-way junction DNA as binding inhibitor of influenza virus hemagglutinin. Bioconjugate Chem. 2018, 29, 1490–1494.
103. Nielsen, P. E.; Egholm, M.; Berg, R. H.; Buchardt, O. Sequence-selective recognition of DNA by strand displacement with a thymine-substituted polyamide. Science 1991, 254, 1497–1500.
104. Nielsen, P. E.; Haaima, G. Peptide nucleic acid (PNA). A DNA mimic with a pseudopeptide backbone. Chem. Soc. Rev. 1997, 26, 73–78.
105. Egholm, M.; Buchardt, O.; Christensen, L.; Behrens, C.; Freier, S. M.; Driver, D. A.; Berg, R. H.; Kim, S. K.; Norden, B.; Nielsen, P. E. PNA hybridizes to complementary oligonucleotides obeying the Watson–Crick hydrogen-bonding rules. Nature 1993, 365, 566–568.
106. Eriksson, M.; Nielsen, P. E. Solution structure of a peptide nucleic acid–DNA duplex. Nat. Struct. Biol. 1996, 3, 410–413.
107. Dubel, N.; Liese, S.; Scherz, F.; Seitz, O. Exploring the limits of bivalency by DNA-based spatial screening. Angew. Chem. Int. Ed. 2019, 58, 907–911.
108. Gorska, K.; Huang, K.-T.; Chaloin, O.; Winssinger, N. DNA-templated homo- and heterodimerization of peptide nucleic acid encoded oligosaccharides that mimick the carbohydrate epitope of HIV. Angew. Chem. Int. Ed. 2009, 48, 7695–7700.
109. Marczynke, M.; Gröger, K.; Seitz, O. Selective binders of the tandem Src homology 2 domains in Syk and Zap70 protein kinases by DNA-programmed spatial screening. Bioconjugate Chem. 2017, 28, 2384–2392.
110. Scheibe, C.; Bujotzek, A.; Dernedde, J.; Weber, M.; Seitz, O. DNA-programmed spatial screening of carbohydrate-lectin interactions. Chem. Sci. 2011, 2, 770–775.
111. Bandlow, V.; Lauster, D.; Ludwig, K.; Hilsch, M.; Reiter-Scherer, V.; Rabe, J. P.; Böttcher, C.; Herrmann, A.; Seitz, O. Sialyl-LacNAc-PNA⋅DNA concatamers by rolling-circle amplification as multivalent inhibitors of influenza A virus particles. Chembiochem 2019, 20, 159–165.
112. Scheibe, C.; Wedepohl, S.; Riese, S. B.; Dernedde, J.; Seitz, O. Carbohydrate–PNA and aptamer–PNA conjugates for the spatial screening of lectins and lectin assemblies. Chembiochem 2013, 14, 236–250.
113. Kleinau, G.; Müller, A.; Biebermann, H. Oligomerization of GPCRs involved in endocrine regulation. J. Mol. Endocrinol. 2016, 57, R59–R80.
114. Carriba, P.; Navarro, G.; Ciruela, F.; Ferré, S.; Casadó, V.; Agnati, L.; Cortés, A.; Mallol, J.; Fuxe, K.; Canela, E. I.; Lluís, C.; Franco, R. Detection of heteromerization of more than two proteins by sequential BRET-FRET. Nat. Methods 2008, 5, 727–733.
115. Gaitonde, S. A.; González-Maeso, J. Contribution of heteromerization to G protein-coupled receptor function. Curr. Opin. Pharmacol. 2017, 32, 23–31.
116. Zhang, K.; Gao, H.; Deng, R.; Li, J. Emerging applications of nanotechnology for controlling cell-surface receptor clustering. Angew. Chem. Int. Ed. 2019, 58, 4790–4799.
117. Feng, Y.-S.; Xie, C.-Q.; Qiao, W.-L.; Xu, H.-J. Palladium-catalyzed trifluoroethylation of terminal alkynes with 1,1,1-trifluoro-2-iodoethane. Org. Lett. 2013, 15, 936–939.
118. Song, D.; Park, Y.; Yoon, J.; Aman, W.; Hah, J.-M.; Ryu, J.-S. Click approach to the discovery of 1,2,3-triazolylsalicylamides as potent Aurora kinase inhibitors. Biorg. Med. Chem. 2014, 22, 4855–4866.
119. Buckley, D. L.; Gustafson, J. L.; Van Molle, I.; Roth, A. G.; Tae, H. S.; Gareiss, P. C.; Jorgensen, W. L.; Ciulli, A.; Crews, C. M. Small-molecule inhibitors of the interaction between the E3 ligase VHL and HIF1α. Angew. Chem. Int. Ed. 2012, 51, 11463–11467.
120. Chouhan, G.; James, K. CuAAC macrocyclization: High intramolecular selectivity through the use of copper–tris(triazole) ligand complexes. Org. Lett. 2011, 13, 2754–2757.
121. Zhang, Z.; Hejesen, C.; Kjelstrup, M. B.; Birkedal, V.; Gothelf, K. V. A DNA-mediated homogeneous binding assay for proteins and small molecules. J. Am. Chem. Soc. 2014, 136, 11115–11120.
122. Lewis, H.; Perrett, A. J.; Burley, G. A.; Eperon, I. C. An RNA splicing enhancer that does not act by looping. Angew. Chem. Int. Ed. 2012, 51, 9800–9803.
123. Grandjean, C.; Boutonnier, A.; Guerreiro, C.; Fournier, J.-M.; Mulard, L. A. On the preparation of carbohydrate−protein conjugates using the traceless Staudinger ligation. J. Org. Chem. 2005, 70, 7123–7132.
124. Bondebjerg, J.; Xiang, Z.; Bauzo, R. M.; Haskell-Luevano, C.; Meldal, M. A solid-phase approach to mouse melanocortin receptor agonists derived from a novel thioether cyclized peptidomimetic scaffold. J. Am. Chem. Soc. 2002, 124, 11046–11055.
125. Ivkovic, J.; Lembacher-Fadum, C.; Breinbauer, R. A rapid and efficient one-pot method for the reduction of N-protected α-amino acids to chiral α-amino aldehydes using CDI/DIBAL-H. Org. Biomol. Chem. 2015, 13, 10456–10460.
126. Yang, S.; He, J. Heterogeneous asymmetric Henry-Michael one-pot reaction synergically catalyzed by grafted chiral bases and inherent achiral hydroxyls on mesoporous silica surface. Chem. Commun. 2012, 48, 10349–10351.
127. Chorghade, M. S.; Mohapatra, D. K.; Sahoo, G.; Gurjar, M. K.; Mandlecha, M. V.; Bhoite, N.; Moghe, S.; Raines, R. T. Practical syntheses of 4-fluoroprolines. J. Fluorine Chem. 2008, 129, 781–784.
128. Llanes, P.; Rodríguez-Escrich, C.; Sayalero, S.; Pericàs, M. A. Organocatalytic enantioselective continuous-flow cyclopropanation. Org. Lett. 2016, 18, 6292–6295.
129. Hollenstein, M. Synthesis of deoxynucleoside triphosphates that include proline, urea, or sulfonamide groups and their polymerase incorporation into DNA. Chem. - Eur. J. 2012, 18, 13320–13330.
130. Zhang, A.; Schlüter, A. D. Multigram solution-phase synthesis of three diastereomeric tripeptidic second-generation dendrons based on (2S,4S)-, (2S,4R)-, and (2R,4S)-4-aminoprolines. Chem. - Asian J. 2007, 2, 1540–1548.
131. Cui, B.; Yu, J.; Yu, F.-C.; Li, Y.-M.; Chang, K.-J.; Shen, Y. Synthesis of (1R,4R)-2,5-diazabicyclo[2.2.1]heptane derivatives by an epimerization-lactamization cascade reaction. RSC Adv. 2015, 5, 10386–10392.
132. Yao, N.; Xiao, W.; Meza, L.; Tseng, H.; Chuck, M.; Lam, K. S. Structure−activity relationship studies of targeting ligands against breast cancer cells. J. Med. Chem. 2009, 52, 6744–6751.
133. Martínez-Ávila, O.; Hijazi, K.; Marradi, M.; Clavel, C.; Campion, C.; Kelly, C.; Penadés, S. Gold manno-glyconanoparticles: Multivalent systems to block HIV-1 gp120 binding to the lectin DC-SIGN. Chem. - Eur. J. 2009, 15, 9874–9888.
134. Sehad, C.; Shiao, C. T.; Sallam, M. L.; Azzouz, A.; Roy, R. Effect of dendrimer generation and aglyconic linkers on the binding properties of mannosylated dendrimers prepared by a combined convergent and onion peel approach. Molecules 2018, 23, 1890.
135. Tian, X.; Pai, J.; Shin, I. Analysis of density-dependent binding of glycans by lectins using carbohydrate microarrays. Chem. - Asian J. 2012, 7, 2052–2060.
136. Poláková, M.; Beláňová, M.; Mikušová, K.; Lattová, E.; Perreault, H. Synthesis of 1,2,3-triazolo-linked octyl (1→6)-α-D-oligomannosides and their evaluation in mycobacterial mannosyltransferase assay. Bioconjugate Chem. 2011, 22, 289–298.
137. Mukhopadhyay, B.; Kartha, K. P. R.; Russell, D. A.; Field, R. A. Streamlined synthesis of per-O-acetylated sugars, glycosyl iodides, or thioglycosides from unprotected reducing sugars. J. Org. Chem. 2004, 69, 7758–7760.
138. 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. Biorg. Med. Chem. 2013, 21, 912–921.
139. Rodebaugh, R.; Fraser-Reid, B. Evidence for cyclic bromonium ion transfer in electrophilic bromination of alkenes: Reaction of ω-alkenyl glycosides with aqueous N-bromosuccinimide. Tetrahedron 1996, 52, 7663–7678.
140. Balmond, E. I.; Coe, D. M.; Galan, M. C.; McGarrigle, E. M. α-selective organocatalytic synthesis of 2-deoxygalactosides. Angew. Chem. Int. Ed. 2012, 51, 9152–9155.
141. Parry, A. L.; Clemson, N. A.; Ellis, J.; Bernhard, S. S. R.; Davis, B. G.; Cameron, N. R. ‘Multicopy multivalent’ glycopolymer-stabilized gold nanoparticles as potential synthetic cancer vaccines. J. Am. Chem. Soc. 2013, 135, 9362–9365.
142. Gauffeny, F.; Marra, A.; Shi Shun, L. K.; Sinaÿ, P.; Tabeur, C. A novel and convenient method for the removal of a nitrate group at the anomeric position. Carbohydr. Res. 1991, 219, 237–240.
143. Park, S.; Shin, I. Carbohydrate microarrays for assaying galactosyltransferase activity. Org. Lett. 2007, 9, 1675–1678.
144. 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. J. Am. Chem. Soc. 2013, 135, 9055–9077.
145. Kato, H.; Uzawa, H.; Nagatsuka, T.; Kondo, S.; Sato, K.; Ohsawa, I.; Kanamori-Kataoka, M.; Takei, Y.; Ota, S.; Furuno, M.; Dohi, H.; Nishida, Y.; Seto, Y. Preparation and evaluation of lactose-modified monoliths for the adsorption and decontamination of plant toxins and lectins. Carbohydr. Res. 2011, 346, 1820–1826.
146. Anraku, K.; Sato, S.; Jacob, N. T.; Eubanks, L. M.; Ellis, B. A.; Janda, K. D. The design and synthesis of an α-Gal trisaccharide epitope that provides a highly specific anti-Gal immune response. Org. Biomol. Chem. 2017, 15, 2979–2992.
147. Rahkila, J.; Ekholm, F. S.; Ardá, A.; Delgado, S.; Savolainen, J.; Jiménez-Barbero, J.; Leino, R. Novel dextran-supported biological probes decorated with disaccharide entities for investigating the carbohydrate–protein interactions of Gal-3. Chembiochem 2019, 20, 203–209.
148. Cheng, S.; Chang, X.; Wang, Y.; Gao, G. F.; Shao, Y.; Ma, L.; Li, X. Glycosylated enfuvirtide: A long-lasting glycopeptide with potent anti-HIV activity. J. Med. Chem. 2015, 58, 1372–1379.
149. Huang, L.-D.; Adak, A. K.; Yu, C.-C.; Hsiao, W.-C.; Lin, H.-J.; Chen, M.-L.; Lin, C.-C. Fabrication of highly stable glyco-gold nanoparticles and development of a glyco-gold nanoparticle-based oriented immobilized antibody microarray for lectin (GOAL) assay. Chem. - Eur. J. 2015, 21, 3956–3967.
150. Zhou, Z.; Fahrni, C. J. A fluorogenic probe for the copper(I)-catalyzed azide−alkyne ligation reaction: Modulation of the fluorescence emission via 3(n,π*)−1(π,π*) inversion. J. Am. Chem. Soc. 2004, 126, 8862–8863.
151. Gordon, J. A.; Blumberg, S.; Lis, H.; Sharon, N. Purification of soybean agglutinin by affinity chromatography on sepharose-N-ϵ-aminocaproyl-β-D-galactopyranosylamine. FEBS Lett. 1972, 24, 193–196.
152. Huang, S.-F.; Lin, C.-H.; Lai, Y.-T.; Tsai, C.-L.; Cheng, T.-J. R.; Wang, S.-K. Development of Pseudomonas aeruginosa lectin LecA inhibitor by using bivalent galactosides supported on polyproline peptide scaffolds. Chem. - Asian J. 2018, 13, 686–700.