Modular synthesis of multivalent glycoarchitectures and their unique selectin binding behavior

Papp, Ilona; Dernedde, Jens; Enders, Sven; Haag, Rainer

doi:10.1039/b813414f

Cited by 91 publications

(75 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Tethering and rolling of leukocytes mediated by binding to their respective carbohydrate ligands on endothelial cells prime leukocytes for firm adhesion and subsequent extravasation. In a recent study, we showed that galactose functionalized polyglycerol dendrimers were able to bind the three selectins, but with low affinity (21). In contrast sulfation of the carbohydrate tuned the selectivity of the polymer toward L-and P-selectin and IC 50 values decreased by (B) Reduction of neutrophil extravasation, as measured by specific elastase activity from ear homogenates.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Dendritic polyglycerol sulfates as multivalent inhibitors of inflammation

Dernedde

Rausch

Weinhart

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

247

294

View full text Add to dashboard Cite

Adhesive interactions of leukocytes and endothelial cells initiate leukocyte migration to inflamed tissue and are important for immune surveillance. Acute and chronic inflammatory diseases show a dysregulated immune response and result in a massive efflux of leukocytes that contributes to further tissue damage. Therefore, targeting leukocyte trafficking may provide a potent form of antiinflammatory therapy. Leukocyte migration is initiated by interactions of the cell adhesion molecules E-, L-, and P-selectin and their corresponding carbohydrate ligands. Compounds that efficiently address these interactions are therefore of high therapeutic interest. Based on this rationale we investigated synthetic dendritic polyglycerol sulfates (dPGS) as macromolecular inhibitors that operate via a multivalent binding mechanism mimicking naturally occurring ligands. dPGS inhibited both leukocytic L-selectin and endothelial P-selectin with high efficacy. Size and degree of sulfation of the polymer core determined selectin binding affinity. Administration of dPGS in a contact dermatitis mouse model dampened leukocyte extravasation as effectively as glucocorticoids did and edema formation was significantly reduced. In addition, dPGS interacted with the complement factors C3 and C5 as was shown in vitro and reduced C5a levels in a mouse model of complement activation. Thus, dPGS represent an innovative class of a fully synthetic polymer therapeutics that may be used for the treatment of inflammatory diseases.anti-inflammatory drug | complement inhibition | multiple target binding | multivalent selectin inhibitor | synthetic polymer

show abstract

Section: Discussionmentioning

confidence: 99%

“…S1) that allows the determination of IC 50 values for inhibitory compounds over a large concentration range (pM-mM) (20,21). Initially, we analyzed the selectin specificity of dPGS.…”

mentioning

confidence: 99%

Dendritic polyglycerol sulfates as multivalent inhibitors of inflammation

Dernedde

Rausch

Weinhart

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

247

294

View full text Add to dashboard Cite

show abstract

“…45) for the inhibition of L-and P-selectins, a general class of receptors which displays a selective adhesion and includes a lectin-like domain. [210] Two structures were compared, namely, free PG-galactose (R ¼ H in Fig. 44) and PG-sulfated galactose (R ¼ SO 3 Na).…”

Section: Negatively Charged Derivatesmentioning

confidence: 99%

Dendritic Polyglycerols for Biomedical Applications

et al. 2009

Self Cite

View full text Add to dashboard Cite

The application of nanotechnology in medicine and pharmaceuticals is a rapidly advancing field that is quickly gaining acceptance and recognition as an independent area of research called "nanomedicine". Urgent needs in this field, however, are biocompatible and bioactive materials for antifouling surfaces and nanoparticles for drug delivery. Therefore, extensive attention has been given to the design and development of new macromolecular structures. Among the various polymeric architectures, dendritic ("treelike") polymers have experienced an exponential development due to their highly branched, multifunctional, and well-defined structures. This Review describes the diverse syntheses and biomedical applications of dendritic polyglycerols (PGs). These polymers exhibit good chemical stability and inertness under biological conditions and are highly biocompatible. Oligoglycerols and their fatty acid esters are FDA-approved and are already being used in a variety of consumer applications, e.g., cosmetics and toiletries, food industries, cleaning and softening agents, pharmaceuticals, polymers and polymer additives, printing photographing materials, and electronics. Herein, we present the current status of dendritic PGs as functional dendritic architectures with particular focus on their application in nanomedicine, in drug, dye, and gene delivery, as well as in regenerative medicine in the form of non-fouling surfaces and matrix materials.

show abstract

“…To provide valuable information about multivalent binding, we synthesized hyperbranched polyglycerol cores with different functionalizations, chain lengths, and degrees of carbohydrate shell functionalities. Recently, [22] we reported the synthesis of galactose neoglycopolymers by a Cu I -catalyzed Huisgen 1,3-dipolar cycloaddition process. Our approach involved the grafting of sugar azides onto a polyalkyne clickable scaffold that was successfully used for selectin inhibition studies.…”

Section: Introductionmentioning

confidence: 99%

“…[26a] The functionalization of hPG and Man derivatives were achieved by employing previously reported experimental conditions. Initially, a fraction of free hydroxyl groups on the hPG core (M n = 5 kDa) were converted either to propargyl ethers [22] with controlled and varied degrees of functionalization 1-3 (15, 50, and 90 %), or the hydroxyl groups were transformed into azides [27] (4-6) with the same functionalities as mentioned above (Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

Multivalent Presentation of Mannose on Hyperbranched Polyglycerol and their Interaction with Concanavalin A Lectin

et al. 2011

Self Cite

View full text Add to dashboard Cite

We describe the synthesis of multivalent mannose derivatives by using hyperbranched polyglycerols (hPG) as a scaffold with different linker structures. Grafting of protected mannose (Man) units is achieved by using Cu(I) -catalyzed Huisgen click chemistry with either an anomeric azide or propargyl ether onto complementarily functionalized alkyne or azido polymer surfaces. NMR spectroscopy, dynamic light scattering (DLS), IR spectroscopy, size-exclusion chromatography (SEC), and elemental analysis have been used to characterize the hPG-Man compounds. The surface availability and bioactivity of Man-modified polymers were evaluated by using a competitive surface plasmon resonance (SPR)-based binding assay by interactions of the glycopolymers with concanavalin A (Con A), a lectin that binds mannose containing molecules. The results indicated that the novel glycoarchitectures presented in this work are efficient inhibitors of Con A-mannose recognition and resulted in inhibitor concentrations (mean IC(50)) from the micro- to the nanomolar range, whereas the corresponding monovalent mannoside (methyl-Man) requires millimolar concentrations. The results provide an interesting structure-activity relationship for libraries of materials that differ in the linkage of the sugar moiety presented on a biocompatible polyglycerol scaffold.

show abstract

Modular synthesis of multivalent glycoarchitectures and their unique selectin binding behavior

Cited by 91 publications

References 33 publications

Dendritic polyglycerol sulfates as multivalent inhibitors of inflammation

Dendritic polyglycerol sulfates as multivalent inhibitors of inflammation

Dendritic Polyglycerols for Biomedical Applications

Multivalent Presentation of Mannose on Hyperbranched Polyglycerol and their Interaction with Concanavalin A Lectin

Contact Info

Product

Resources

About