Recognition Specificity of Neoglycopolymers Prepared by Ring-Opening Metathesis Polymerization

Mortell, Kathleen H.; Weatherman, Ross; Kiessling, Laura L.

doi:10.1021/ja953574q

Cited by 270 publications

(197 citation statements)

References 14 publications

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“…[153] Polymers generated by ROMP have found increasing use as biologically active multivalent ligands. [101,149,[154][155][156][157][158] Ruthenium carbene catalysts for ROMP can be used to generate materials of distinct valency. [150,[159][160][161] These ligands have been generated as inhibitors of saccharide-protein interactions, [151,[162][163][164] as ligands for combating vancomycin-resistant bacteria, [156] and as effectors of biological responses.…”

Section: 3dmentioning

confidence: 99%

Synthetic Multivalent Ligands as Probes of Signal Transduction

2006

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Cell surface receptors acquire information from the extracellular environment and coordinate intracellular responses. Evidence from biochemical and structural studies indicates that many receptors do not operate as individual entities, but rather as part of higher-order complexes (e.g. dimers and oligomers). Coupling the functions of multiple receptors may endow signaling pathways with the sensitivity and malleability required to govern cellular responses. Moreover, multireceptor signaling complexes may provide a means of spatially segregating otherwise degenerate signaling cascades. Despite the proposed importance of receptor-receptor processes in cellular signaling, questions concerning the mechanisms, extent, and consequences of receptor co-localization and interreceptor communication remain unanswered.Chemical synthesis can provide a variety of compounds with which to address the role of receptor assembly in signal transduction. The focus of this review is one such approach -the use of synthetic multivalent ligands to characterize receptor function. Multivalent ligands can be generated that possess a variety of sizes, shapes, valencies, orientations, and densities of binding elements. Their unique architectures imbue multivalent ligands with the ability to access binding modes not available to monovalent compounds. Multivalent ligands, therefore, are capable of illuminating aspects of inter-receptor processes that are not readily probed using conventional approaches. We suggest that, as focus shifts from investigations of the function of individual proteins and toward the analysis of multi-receptor signaling complexes, multivalent ligands will become even more valuable tools with which to ask sophisticated mechanistic questions. Further, multivalent ligands may provide new opportunities for manipulating receptor systems for the deconvolution of pathways, diagnosis, and, ultimately, the treatment of disease.

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Section: 3dmentioning

confidence: 99%

Synthetic Multivalent Ligands as Probes of Signal Transduction

2006

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“…77 Many multivalent inhibitors, including neoglycopolymers, have been synthesized for biological applications. 78,79 Dendrimers are attractive scaffolds for constructing multivalent ligands because of their globular shape and the high local density of ligand presentation on the surface. 80 -82 By applying our chain-walking methodology, we found that the simple copolymerization of ethylene with a mannose-containing comonomer (13) at a low value of P E and a low comonomer concentration resulted in a mannose-coated dendritic copolymer.…”

Section: Chain Walking: a New Strategy For Controlling Polymer Topologymentioning

confidence: 99%

Z. Guan, Control of polymer topology through late‐transition‐metal catalysis, J Polym Sci Part A: Polym Chem (2003), 41(22), 3680–3692

Guan

2003

J. Polym. Sci. A Polym. Chem.

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ABSTRACT:In this article, recent examples are reviewed of late-transition-metal catalysis applied to polymer topology control. By the judicious selection or design of latetransition-metal catalysts, polymers with a broad range of topologies, including linear, short-chain-branched, hyperbranched, dendritic, and cyclic topologies, have been successfully synthesized. A distinctive advantage of the catalyst approach is that polymers with complex topologies can be prepared in one pot from simple commercial monomers. A fundamental difference of the catalyst approach with respect to other approaches is that the polymer topology is controlled by the catalysts instead of the monomer structure. In our own laboratory, we have successfully used two strategies to control the polymer topology with late-transition-metal catalysts. In the first strategy, hyperbranched polymers are prepared by the direct free-radical polymerization of divinyl monomers through control of the competition between propagation and chain transfer with a cobalt chain-transfer catalyst. In the second strategy, polyethylene topology is successfully controlled by the regulation of the competition between propagation and chain walking with the Brookhart Pd II -␣-bisimine catalyst.

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“…Investigators have previously observed greater specificity on the part of lectins for polyvalent ligands as compared with their monovalent counterparts (15)(16)(17)(18)(19)(20)(21)(22). The specificity for multivalent ligands has been attributed to a requirement for unique spacing patterns (15)(16)(17)(18), secondary protein-protein and protein-carbohydrate interactions (19,20), and amplification in the polyvalent state of small differences in the affinities between monovalent forms (21). One prediction of a model in which small differences in affinity of monovalent ligands are amplified in the polyvalent state is that the affinities obtained for Mu11 binding to immobilized S4GGnM-BSA and S3GGnM-BSA would differ but that the B max obtained at saturation would be the same.…”

Section: Specificity Of the Cys-rich Domain For Monovalent Ligands-wementioning

confidence: 99%

The Mannose/N-Acetylgalactosamine-4-SO4Receptor Displays Greater Specificity for Multivalent than Monovalent Ligands

Roseman

Baenziger²

2001

Journal of Biological Chemistry

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Recognition of carbohydrates on glycosylated molecules typically requires multivalent interactions with receptors. Monovalent forms of terminal saccharides engaged by the receptor binding sites typically display weak affinities in the mM range and poor specificity. In contrast, multivalent forms of the same saccharides are bound with strong affinity (10 ؊7 -10 ؊9 M) and significantly greater specificity. Although multivalency can readily account for increased affinity, the molecular basis for enhanced specificity is not well understood. We have examined the specificity of the cysteine-rich domain of the mannose/GalNAc-4-SO 4 receptor using monovalent and multivalent forms of the trisaccharide GalNAc␤1,4GlcNAc␤1,2Man␣ (GGnM) sulfated at either the C4 (S4GGnM) or C3 ( We previously demonstrated that glycoproteins such as LH 1 and thyrotropin bearing N-linked oligosaccharides terminating with ␤1,4-linked GalNAc-4-SO 4 are recognized by a receptor located in hepatic endothelial cells, the Man/GalNAc-4-SO 4 receptor, and are rapidly removed from the circulation (1-4). Rapid clearance in conjunction with stimulated release from dense core storage granules in LH-producing cells located in the anterior lobe of the pituitary produce the episodic rise and fall in serum LH levels that is important for the expression of LH bioactivity in vivo. A novel feature of the Man/GalNAc-4-SO 4 receptor is its capacity to bind carbohydrate moieties terminating with Man and GalNAc-4-SO 4 at physically distinct domains that are not structurally related. The binding site for GalNAc-4-SO 4 is located in the cysteine-rich domain found at the N terminus of the Man/GalNAc-4-SO 4 receptor (5). The Cys-rich domain is a member of the ␤-trefoil family of proteins that includes proteins such as acidic fibroblast growth factor. The binding site is a neutral pocket that accommodates the sulfate group, which accounts for the major interactions with the protein (6). Inhibition and modeling studies with monovalent ligands have indicated that the binding site in the Cys-rich domain can also accommodate saccharides with terminal Gal or GalNAc when the sulfate is located at C3 rather than C4 (6, 7).The latter observations were unexpected because we had reported that bovine serum albumin substituted with 6 -8 molecules of SO 4 -4-GalNAc␤1,4GlcNAc␤1,2Man␣ (S4GGnM-BSA) is removed from the circulation at a rate that is at least 12-fold greater than that seen for bovine serum albumin substituted with 6 -8 molecules of SO 4 -3-GalNAc␤1,4GlcNAc␤1,2Man␣ (S3GGnM-BSA). Furthermore, isolated hepatic endothelial cells do not bind and internalize S3GGnM-BSA, and the purified Man/GalNAc-4-SO 4 receptor does not display significant binding of S3GGnM-BSA in precipitation assays (2, 3). We have recently determined that the Man/GalNAc-4-SO 4 receptor must be dimeric and engage at least two terminal GalNAc-4-SO 4 moieties on separate oligosaccharides to mediate uptake by hepatic endothelial cells with a K d of 1.63 ϫ 10 Ϫ7 M (8). These observations raise the possibility th...

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Recognition Specificity of Neoglycopolymers Prepared by Ring-Opening Metathesis Polymerization

Cited by 270 publications

References 14 publications

Synthetic Multivalent Ligands as Probes of Signal Transduction

Synthetic Multivalent Ligands as Probes of Signal Transduction

Z. Guan, Control of polymer topology through late‐transition‐metal catalysis, J Polym Sci Part A: Polym Chem (2003), 41(22), 3680–3692

The Mannose/N-Acetylgalactosamine-4-SO4Receptor Displays Greater Specificity for Multivalent than Monovalent Ligands

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