Multivalent clustering

Whilst it is possible that the enhancement in binding is a result of chelation or a combination of an increased local concentration facilitating a bind and jump mechanism as seen with lectins, specific binding modes for glycosidases have been proposed. In particular, the presence of non-catalytic carbohydrate binding sites on the enzyme may allow a multivalent cluster to bind at more than one site [10]. 

To better understand the critical role of oligosaccharide-receptor interactions and their molecular mechanisms through the cluster-effect, and thus access optimized synthetic ligands, several research groups have shown creativity in proposing original multivalent platforms that could allow for tailored valencies, dimensions, and epitope orientations. 

Historically, the first multivalent glycoconjugate obtained by metal-assisted self-assembly was described in 1994 by Sakai and Sasaki (Fig. 35).267 The methodology was based on the trimerization of unsymmetrical Bipy-GalNAc (307) induced by the presence of Fe(II) salts, to give the tridentate Fen(bipy-GalNAc)3 cluster 308 as a mixture of four diastereomeric isomers (A-fac, A-fac, A-mer, and A-mer). 

S. Kotter, U. Krallman-Wenzel, S. Ehlers, and T. B. Lindhorst, Multivalent ligands for the mannose-specific lectin on type 1 fimbriae of Escherichia coli Syntheses and testing of trivalent y-D-mannoside clusters, J. Chem. Soc. Perkin Trans., 1 (1998) 2193-2200. 

A. Patel and T. B. Lindhorst, Multivalent glycomimetics Synthesis of nonava-lent mannoside clusters with variation of spacer properties, Carbohydr. Res., 341 (2006) 1657-1668. 

R. Roy, M. Corazon Trono, and D. Giguere, Effects of linker rigidity and orientation of mannoside clusters for multivalent interactions with proteins, in R. Roy, (Ed), Glycomimetics Modern Synthetic Methodologies, ACS Symp. Ser., 896 (2005) 137-150. 

A. Dondoni, M. Kleban, X. Hu, A. Marra, and H. D. Banks, Glycoside-clustering round calixarenes toward the development of multivalent carbohydrate ligands. Synthesis and conformational analysis of calix[4]arene O- and C-glycoconjugates, J. Org. Chem., 67 (2002) 4722 -733. 

C. Ortiz Mellet, J. Defaye, and J. M. Garcia Fernandez, Multivalent cyclooligosaccharides Versatile carbohydrate clusters with dual role as molecular receptors and lectin ligands, Chem. Eur. J., 8 (2002) 1983-1990. 

T. K. Lindhorst, C. Kieburg, and U. Krallmann-Wenzel, Inhibition of the type 1 fimbriae-mediated adhesion of Escherichia coli to erythrocytes by multiantenn-ary x-mannosyl clusters the effect of multivalency, Glycoconjug. /., 15 (1998) 605-613. 

O. Srinivas, S. Radhika, N. M. Bandaru, S. K. Nadimpalli, and N. Jayaraman, Synthesis and biological evaluation of mannose-6-phosphate-coated multivalent dendritic cluster glycosides, Org. Biomol. Chem., 3 (2005) 4252-4257. 

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