Details
| Original language | English |
|---|---|
| Pages (from-to) | 1088-1098 |
| Number of pages | 11 |
| Journal | Macromolecular Bioscience |
| Volume | 11 |
| Issue number | 8 |
| Early online date | 3 Jun 2011 |
| Publication status | Published - 11 Aug 2011 |
| Externally published | Yes |
Abstract
L-, P-, and E-Selectin are cell adhesion molecules that play a crucial role in leukocyte recruitment from the blood stream to the afflicted tissue in an acute and chronic inflammatory setting. Since selectins mediate the initial contact of leukocytes to the vascular endothelium, they have evolved as a valuable therapeutic target in diseases related to inflammation by inhibition of the physiological selectin-ligand interactions. In a previous study, it was demonstrated that dPGS, a fully synthetic heparin analogue, works as an efficient inhibitor towards L- and P-selectin in vitro as well as in vivo. Herein, the focus is directed towards the effect of size and charge density of the polyanion. The efficiency of L-selectin inhibition via an SPR-based in vitro assay and a cell-based flow chamber assay is investigated with dPGS ranging from approximately 4 to 2000kDa. SPR measurements show that the inhibitory potential of highly sulfated dPGS increases with size and charge density. Thereby, IC 50 values from the micromolar to the low picomolar range are determined. The same tendency could be observed in a cell-based flow chamber assay with three representative dPGS samples. This structure-affinity relationship of dPGS suggests that the strong inhibitory potential of dPGS is not only based on the strong electrostatic interaction with areas of cationic surface potential on L-selectin but is also due to a steric shielding of the carbohydrate binding site by large, flexible dPGS particles. Polysulfated, flexible inhibitors to L-selectin are investigated. In inflammation, selectins mediate leukocyte recruitment from the blood stream to the vessel wall. Therefore, they have evolved into a promising target in anti-inflammatory therapy. Size and surface charge density of the polyelectrolytes is correlated with their efficiency to multivalently bind to L-selectin and hence act as inhibitor in a competitive in vitro assay.
Keywords
- Hyperbranched polymers, Multivalency, Polyelectrolytes, Selectin inhibition
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Biotechnology
- Chemical Engineering(all)
- Bioengineering
- Materials Science(all)
- Biomaterials
- Materials Science(all)
- Polymers and Plastics
- Materials Science(all)
- Materials Chemistry
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In: Macromolecular Bioscience, Vol. 11, No. 8, 11.08.2011, p. 1088-1098.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - The Role of Dimension in Multivalent Binding Events
T2 - Structure-Activity Relationship of Dendritic Polyglycerol Sulfate Binding to L-Selectin in Correlation with Size and Surface Charge Density
AU - Weinhart, Marie
AU - Gröger, Dominic
AU - Enders, Sven
AU - Riese, Sebastian B.
AU - Dernedde, Jens
AU - Kainthan, Rajesh K.
AU - Brooks, Donald E.
AU - Haag, Rainer
PY - 2011/8/11
Y1 - 2011/8/11
N2 - L-, P-, and E-Selectin are cell adhesion molecules that play a crucial role in leukocyte recruitment from the blood stream to the afflicted tissue in an acute and chronic inflammatory setting. Since selectins mediate the initial contact of leukocytes to the vascular endothelium, they have evolved as a valuable therapeutic target in diseases related to inflammation by inhibition of the physiological selectin-ligand interactions. In a previous study, it was demonstrated that dPGS, a fully synthetic heparin analogue, works as an efficient inhibitor towards L- and P-selectin in vitro as well as in vivo. Herein, the focus is directed towards the effect of size and charge density of the polyanion. The efficiency of L-selectin inhibition via an SPR-based in vitro assay and a cell-based flow chamber assay is investigated with dPGS ranging from approximately 4 to 2000kDa. SPR measurements show that the inhibitory potential of highly sulfated dPGS increases with size and charge density. Thereby, IC 50 values from the micromolar to the low picomolar range are determined. The same tendency could be observed in a cell-based flow chamber assay with three representative dPGS samples. This structure-affinity relationship of dPGS suggests that the strong inhibitory potential of dPGS is not only based on the strong electrostatic interaction with areas of cationic surface potential on L-selectin but is also due to a steric shielding of the carbohydrate binding site by large, flexible dPGS particles. Polysulfated, flexible inhibitors to L-selectin are investigated. In inflammation, selectins mediate leukocyte recruitment from the blood stream to the vessel wall. Therefore, they have evolved into a promising target in anti-inflammatory therapy. Size and surface charge density of the polyelectrolytes is correlated with their efficiency to multivalently bind to L-selectin and hence act as inhibitor in a competitive in vitro assay.
AB - L-, P-, and E-Selectin are cell adhesion molecules that play a crucial role in leukocyte recruitment from the blood stream to the afflicted tissue in an acute and chronic inflammatory setting. Since selectins mediate the initial contact of leukocytes to the vascular endothelium, they have evolved as a valuable therapeutic target in diseases related to inflammation by inhibition of the physiological selectin-ligand interactions. In a previous study, it was demonstrated that dPGS, a fully synthetic heparin analogue, works as an efficient inhibitor towards L- and P-selectin in vitro as well as in vivo. Herein, the focus is directed towards the effect of size and charge density of the polyanion. The efficiency of L-selectin inhibition via an SPR-based in vitro assay and a cell-based flow chamber assay is investigated with dPGS ranging from approximately 4 to 2000kDa. SPR measurements show that the inhibitory potential of highly sulfated dPGS increases with size and charge density. Thereby, IC 50 values from the micromolar to the low picomolar range are determined. The same tendency could be observed in a cell-based flow chamber assay with three representative dPGS samples. This structure-affinity relationship of dPGS suggests that the strong inhibitory potential of dPGS is not only based on the strong electrostatic interaction with areas of cationic surface potential on L-selectin but is also due to a steric shielding of the carbohydrate binding site by large, flexible dPGS particles. Polysulfated, flexible inhibitors to L-selectin are investigated. In inflammation, selectins mediate leukocyte recruitment from the blood stream to the vessel wall. Therefore, they have evolved into a promising target in anti-inflammatory therapy. Size and surface charge density of the polyelectrolytes is correlated with their efficiency to multivalently bind to L-selectin and hence act as inhibitor in a competitive in vitro assay.
KW - Hyperbranched polymers
KW - Multivalency
KW - Polyelectrolytes
KW - Selectin inhibition
UR - http://www.scopus.com/inward/record.url?scp=79961051181&partnerID=8YFLogxK
U2 - 10.1002/mabi.201100051
DO - 10.1002/mabi.201100051
M3 - Article
C2 - 21648090
AN - SCOPUS:79961051181
VL - 11
SP - 1088
EP - 1098
JO - Macromolecular Bioscience
JF - Macromolecular Bioscience
SN - 1616-5187
IS - 8
ER -