Abstract:Glycopolymers mimicking GM1 gangliosides were synthesized by incorporating multiple types of carbohydrates into the polymer backbone. The glycopolymers were immobilized onto gold surfaces, and the interactions with the cholera toxin B subunit (CTB) were analyzed using surface plasmon resonance imaging. The glycopolymer containing both galactose and neuraminic acid showed enhanced recognition of CTB. The interaction was enhanced mainly because of an improvement in the dissociation process by the binding of the … Show more
“…Underestimating the latter can totally offset the enthalpic benefit of cooperativity due to the entropic penalty associated with linker flexibility. 58,59 Recently, Zentel and coworkers 60 and Tacke and coworkers 61 conveyed compelling evidence of the potential of mimicking the selectin recognition properties of the sialyl Lewis x (SLe x ) tetrasaccharide (NeuNAc-a(2-3)-Gal-b(1-4)-[Fuc-a(1-3)]-GlcNAc) by the carbohydrate module approach for biomedical applications. Selectins are a family of cell adhesion molecules with an extracellular lectin domain that bind to fucosylated and sialylated glycoproteins and play a key role in the innate immune response.…”
Section: Carbohydrate-lectin Interactions In Heterogeneous Environmenmentioning
It has been amply constated that sugar ligand multivalency increases lectin-binding avidities dramatically, thereby modulating the capacity of carbohydrates to participate in supramolecular recognition processes involving transfer of biological information. The importance of this concept, the multivalent or glycoside cluster effect, in cell biology in general and in the glycosciences in particular is reflected in the ever-growing number of papers in the field. An impressive range of glycoarchitectures has been conceived to imitate the glycan coating of cells (the glycocalyx) in order to target complementary lectin receptors. However, these models rarely address the heterogeneity and the fluidity of the densely glycosylated cell membrane. They also disregard the impact that high-density nanosized arrangements could have in their interactions with the whole spectrum of carbohydrate-interacting proteins, among which glycosidases are notable representatives. For many years it has been tacitly assumed that:(i) efficient recognition by lectins generally requires high densities of the putative primary ligand and (ii) the mechanisms governing binding of a carbohydrate motif by a lectin or a glycosidase are totally disparate.Notwithstanding, an increasing amount of evidence seriously questions this paradigm. First, it was shown that secondary ''innocent'' ligands can play important roles in the recognition of heteroglycocluster constructs by lectins through synergistic or antagonistic contributions, a phenomenon termed the heterocluster effect. Second, the existence of multivalent effects in the inhibition of certain glycosidases by glycomimetic-and, even more disturbing, glyco-coated architectures (multivalent enzyme inhibition) was demonstrated. These observations call for a generalized multivalent effect governing the supramolecular chemistry of carbohydrate or glycomimetic structures in a biological context, with (hetero)multivalency acting as a multimodal switcher to drive the encoded information through different pathways. In this Feature Article we review the advancements made in the last few years in our understanding of the mechanisms underpinning the generalized multivalent effect, with an emphasis on the potential risks and opportunities derived from (hetero)multivalency-elicited promiscuity.
“…Underestimating the latter can totally offset the enthalpic benefit of cooperativity due to the entropic penalty associated with linker flexibility. 58,59 Recently, Zentel and coworkers 60 and Tacke and coworkers 61 conveyed compelling evidence of the potential of mimicking the selectin recognition properties of the sialyl Lewis x (SLe x ) tetrasaccharide (NeuNAc-a(2-3)-Gal-b(1-4)-[Fuc-a(1-3)]-GlcNAc) by the carbohydrate module approach for biomedical applications. Selectins are a family of cell adhesion molecules with an extracellular lectin domain that bind to fucosylated and sialylated glycoproteins and play a key role in the innate immune response.…”
Section: Carbohydrate-lectin Interactions In Heterogeneous Environmenmentioning
It has been amply constated that sugar ligand multivalency increases lectin-binding avidities dramatically, thereby modulating the capacity of carbohydrates to participate in supramolecular recognition processes involving transfer of biological information. The importance of this concept, the multivalent or glycoside cluster effect, in cell biology in general and in the glycosciences in particular is reflected in the ever-growing number of papers in the field. An impressive range of glycoarchitectures has been conceived to imitate the glycan coating of cells (the glycocalyx) in order to target complementary lectin receptors. However, these models rarely address the heterogeneity and the fluidity of the densely glycosylated cell membrane. They also disregard the impact that high-density nanosized arrangements could have in their interactions with the whole spectrum of carbohydrate-interacting proteins, among which glycosidases are notable representatives. For many years it has been tacitly assumed that:(i) efficient recognition by lectins generally requires high densities of the putative primary ligand and (ii) the mechanisms governing binding of a carbohydrate motif by a lectin or a glycosidase are totally disparate.Notwithstanding, an increasing amount of evidence seriously questions this paradigm. First, it was shown that secondary ''innocent'' ligands can play important roles in the recognition of heteroglycocluster constructs by lectins through synergistic or antagonistic contributions, a phenomenon termed the heterocluster effect. Second, the existence of multivalent effects in the inhibition of certain glycosidases by glycomimetic-and, even more disturbing, glyco-coated architectures (multivalent enzyme inhibition) was demonstrated. These observations call for a generalized multivalent effect governing the supramolecular chemistry of carbohydrate or glycomimetic structures in a biological context, with (hetero)multivalency acting as a multimodal switcher to drive the encoded information through different pathways. In this Feature Article we review the advancements made in the last few years in our understanding of the mechanisms underpinning the generalized multivalent effect, with an emphasis on the potential risks and opportunities derived from (hetero)multivalency-elicited promiscuity.
“…Previously, we reported that Fuc 100 and Gal 50 Fuc 50 block CTB binding to a fucosylated glycan, triLe x , but Gal 100 does not and that Gal 100 blocks CTB binding to GM1 but Gal 50 Fuc 50 does not . The incomplete blocking of GM1 binding to CTB by Gal 100 may have been because of the fact that the Gal of CTB-Gal 100 does not have multiple points of interaction like GM1 has with CTB . Blocking of CTB binding to the human primary intestinal epithelium can be accomplished with both galactosylated and fucosylated polymers …”
The canonical binding site on the B subunit of cholera toxin (CTB) binds to GM1 gangliosides on host cells. However, the recently discovered noncanonical binding site on CTB with affinity for fucosylated molecules has raised the possibility that both sites can be involved in initiating intoxication. Previously, we showed that blocking CTB binding to human and murine small intestine epithelial cells can be increased by simultaneously targeting both binding sites with multivalent norbornene-based glycopolymers [ACS Infect. Dis. 2020, 6, 5, 1192−1203. However, the mechanistic origin of the increased blocking efficacy was unclear. Herein, we observed that mixing CTB pentamers and glycopolymers that display fucose and galactose sugars results in the formation of large aggregates, which further inhibits binding of CTB to human granulocytes. Dynamic light scattering analysis, small-angle X-ray scattering analysis, transmission electron microscopy, and turbidimetric assays revealed that the facial directionality of CTB promotes interchain cross-linking, which in turn leads to self-assembly of protein−polymer networks. This cross-linking-induced selfassembly occurs only when the glycopolymer system contains both galactose and fucose. In an assay of the glycopolymer's ability to block CTB binding to human granulocytes, we observed a direct correlation between IC 50 and self-assembly size. The aggregation mechanism of inhibition proposed herein has potential utility for the development of low-cost macromolecular clinical therapeutics for cholera that do not have exotic architectures and do not require complex synthetic sequences.
“…Thus, the preparation of a biomimetic glycocalyxlike surface can provide a general strategy to obtain biomedical materials with good hydrophilicity, biocompatibility, and specific biomolecule recognition. 46,[106][107][108][109][110][111][112][113][114][115][116][117][118][119][120][121] In general, the preparation routes of a glycocalyx-like surface, i.e., glycosylation methods, can be divided into physical methods (e.g., physical adsorption and dipcoating), chemical methods (e.g., surface modification by glycopolymers, surface initiated polymerization of glycomonomers, and synthesis glycopolymers to prepare the substrates), and biochemical methods (e.g., enzymatic transglycosylation). 54,[122][123][124][125][126][127] For example, Bojarova et al reviewed the preparation routes and biomedical applications of glycomaterials (e.g., glyconanoparticles and glycodendrimers) based on the specific lectincarbohydrate interactions.…”
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