Dendritic polyglycerol sulfates as multivalent inhibitors of inflammation.
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 anti-inflammatory 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.
Zentralinstitut für Laboratoriumsmedizin und Pathobiochemie, Charité-Universitätsmedizin, 12203 Berlin, Germany.
Jens
J
Dernedde
Alexandra
A
Rausch
Marie
M
Weinhart
Sven
S
Enders
Rudolf
R
Tauber
Kai
K
Licha
Michael
M
Schirner
Ulrich
U
Zügel
Arne
A
von Bonin
Rainer
R
Haag
D000706:Anaphylatoxins / Q000096:biosynthesis; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D050091:Dendrimers / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D003877:Dermatitis, Contact / Q000150:complications / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D005260:Female; D005990:Glycerol / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D019041:L-Selectin / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects; D051379:Mice; D018448:Models, Immunological; D019007:P-Selectin / Q000378:metabolism; D011108:Polymers / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011485:Protein Binding / Q000187:drug effects; D013431:Sulfates / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
D000706:Anaphylatoxins; D000893:Anti-Inflammatory Agents; D050091:Dendrimers; D019007:P-Selectin; D011108:Polymers; D013431:Sulfates; D019041:L-Selectin; C043941:polyglycerol; D005990:Glycerol