Polypeptide-Based Glycopolymers for the Study of Multivalent Binding Events

Maheshwari, Ronak; Liu, Shuang; Polizzotti, Brian D.; Wang, Ying; Kiick, Kristi L.

doi:10.1021/bk-2008-0990.ch014

Cited by 5 publications

(8 citation statements)

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“…Many different synthetic architectures such as glycopeptides, globular glycomacromolecules (dendrimers), or linear glycopolymers have been successfully used for the multivalent presentation of carbohydrate ligands mimicking the cluster-glycoside effect . It has also been shown in literature that the presenting scaffold has an important influence on the multivalent binding mode. − Binding affinity and selectivity can be controlled through variation of number, density, and spacing of ligands. ,,− Furthermore, the scaffold itself can contribute to the binding through secondary interactions, for example, hydrophobic interactions, and thus vary the ligand–receptor interactions. Nevertheless, most synthetic multivalent ligands are still optimized empirically, especially systems based on polymeric scaffolds.…”

Section: Introductionmentioning

confidence: 99%

Sequence-Defined Glycopolymer Segments Presenting Mannose: Synthesis and Lectin Binding Affinity

et al. 2012

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We present for the first time the synthesis of sequence-defined monodisperse glycopolymer segments via solid-phase polymer synthesis. Functional building blocks displaying alkyne moieties and hydrophilic ethylenedioxy units were assembled stepwise on solid phase. The resulting polymer segments were conjugated with mannose sugars via 1,3-dipolar cycloaddition. The obtained mono-, di-, and trivalent mannose structures were then subject to Con A lectin binding. Surface plasmon resonance studies showed a nonlinear increase in binding regarding the number and spacing of sugar ligands. The results of Con A lectin binding assays indicate that the chemical composition of the polymeric scaffold strongly contributes to the binding activities as well as the spacing between the ligands and the number of presented mannose units. Our approach now allows for the synthesis of highly defined glycooligomers and glycopolymers with a diversity of properties to investigate systematically multivalent effects of polymeric ligands.

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Section: Introductionmentioning

confidence: 99%

Sequence-Defined Glycopolymer Segments Presenting Mannose: Synthesis and Lectin Binding Affinity

et al. 2012

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Section: Discussionmentioning

confidence: 99%

“…11,15 The use of these backbones was further motivated by our related work indicating that specific ligand densities and backbone architectures of multivalent glycopolypeptides can be used to manipulate the binding of multivalent ligands with protein receptors. 27,29,30,33,53 That similar recombinantly derived, polypeptide scaffolds would be useful for studies of cell-surface receptor clustering was suggested by previous work indicating that multivalent ligands with minimal chain length and valencies can be used to address cell surface receptors and control signaling. For example, a 15-mer polynorbornene-based glycopolymer containing 3,6-disulfo-galactose inhibited leukocyte rolling on the surface coated with the natural ligand GlyCAM-1, although with higher IC 50 values than a glycopolymer containing a strong-binding oligosaccharide ligand, 3 0 ,6-disulfo-Le x .…”

Section: Discussionmentioning

confidence: 99%

Architecture effects on L-selectin shedding induced by polypeptide-based multivalent ligands

Liu

Kiick

2011

Polym. Chem.

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Multivalent interactions between selectins and their ligands play key roles in mediating the rolling and tethering of leukocytes in the early steps of the inflammatory response, as well as in lymphocyte circulation. L-selectin shedding, which is the proteolytic cleavage of L-selectin, can be induced by L-selectin clustering through the binding of multivalent ligands to multiple L-selectin molecules, and it has been shown to regulate leukocyte rolling and subsequent integrin activation for firm adhesion. In this paper, we report the production of homogenous glycopolypeptides modified with a 3,6-disulfo-galactopyranoside equipped with a caproyl linker. The saccharide residue was chemically attached to various polypeptide backbones of differing architectures; the composition and purity of the sulfated glycopolypeptides was confirmed via 1H-NMR spectroscopy, amino acid analysis (AAA), and electrophoretic analysis. The retention of the conformation of the polypeptide backbone was confirmed via circular dichroic spectroscopy. The shedding of l-selectin from the surface of Jurkat cells induced by these sulfated glycopolypeptides, determined via ELISA-based methods, varied based on differences in the architectures of the polypeptide scaffolds, suggesting opportunities for these strategies in probing cell-surface receptor arrays and directing cell signaling events.

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“…Polymer platforms are synthetically tractable, enabling fine-tuning to promote a desired activity or to modulate a specific biological process . Specifically, polymer synthesis permits control over length, size, dispersity, flexibility, degradability, ligand presentation, and allows for tailoring of bulk properties. ,, …”

Section: Multivalent Ligands Targeting B Cells To Combat Autoimmunitymentioning

confidence: 99%

Multivalent Scaffolds to Promote B cell Tolerance

et al. 2023

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Autoimmune diseases are characterized by aberrant immune responses toward self-antigens. Current treatments lack specificity, promoting adverse effects by broadly suppressing the immune system. Therapies that specifically target the immune cells responsible for disease are a compelling strategy to mitigate adverse effects. Multivalent formats that display numerous binding epitopes off a single scaffold may enable selective immunomodulation by eliciting signals through pathways unique to the targeted immune cells. However, the architecture of multivalent immunotherapies can vary widely, and there is limited clinical data with which to evaluate their efficacy. Here, we set forth to review the architectural properties and functional mechanisms afforded by multivalent ligands and evaluate four multivalent scaffolds that address autoimmunity by altering B cell signaling pathways. First, we address both synthetic and natural polymer backbones functionalized with a variety of small molecule, peptide, and protein ligands for probing the effects of valency and costimulation. Then, we review nanoparticles composed entirely from immune signals which have been shown to be efficacious. Lastly, we outline multivalent liposomal nanoparticles capable of displaying high numbers of protein antigens. Taken together, these examples highlight the versatility and desirability of multivalent ligands for immunomodulation and illuminate strengths and weaknesses of multivalent scaffolds for treating autoimmunity.

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Polypeptide-Based Glycopolymers for the Study of Multivalent Binding Events

Cited by 5 publications

References 0 publications

Sequence-Defined Glycopolymer Segments Presenting Mannose: Synthesis and Lectin Binding Affinity

Sequence-Defined Glycopolymer Segments Presenting Mannose: Synthesis and Lectin Binding Affinity

Architecture effects on L-selectin shedding induced by polypeptide-based multivalent ligands

Multivalent Scaffolds to Promote B cell Tolerance

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