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DOI: 10.1055/s-2004-815633
Modulation of Antithrombin-Protease Interactions by Semisynthetic Low-Molecular-Weight Heparins with Different Sulfation Patterns
Publication History
Publication Date:
13 January 2004 (online)
ABSTRACT
Heparin, a natural glycosaminoglycan (GAG), is widely used for the treatment of thrombotic diseases. Most of its side effects are related to its ability to bind to different proteins, thus interfering with its target biological activity. To gain insight into structure-activity relationships, we investigated the interaction of a homogeneous series of sulfated polysaccharides, derived from controlled desulfation of a supersulfated low-molecular-weight heparin (LMWH) with the target enzymes human antithrombin (AT) and thrombin (T). In addition, we analyzed the activation process of the serpin AT against T and factor Xa (FXa). A nonlinear correlation between the strength of the AT-heparin complex and the polysaccharide sulfation degree was observed, whereas only a modest modulation of T binding to heparin occurred. The efficiency of the LMWH derivatives in activating AT toward the proteases was generally high for derivatives exhibiting a low dissociation constant. Only the supersulfated heparin showed a serpin activation ability higher than expected from the affinity studies.
Examination of the sulfation pattern in the light of the above results suggests a key role of the substitution of the iduronic acid residue in the heparin-mediated serpin binding and activation processes. Indeed, sulfation at position 2 of the uronic acid is beneficial, whereas 2,3-disubstitution generates unfavorable contacts between the GAG and AT. Glucosamine sulfation at position 6 appears to grant increased catalytic efficiency.
These results indicate that chemical modification of the heparin sulfation pattern can be used to modulate binding specificity and activity toward its biological targets.
KEYWORDS
Glycosaminoglycan - heparin - antithrombin - thrombin - sulfation - polysaccharide
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