Partial synthetic glucan sulfates as potential new antithrombotics: a review.
Structurally defined sulfated polysaccharides were produced by partial synthesis to develop new antithrombotics as potential heparin alternatives. Glucans of different natural origins were used as starting polymers. The resulting glucan sulfates display pronounced anticoagulant effects; some of them are as active as heparin. According to studies on the structure-activity relationships, besides the molecular weight (MW) and the degree of sulfation (DS), the sulfation pattern and the polysaccharide basic structure are crucial parameters for their anticoagulant potency. Their mode of action differs from that of heparin. Depending on their individual structure, they specifically interfere with various stages of the coagulation process. In vivo, they partly exhibit antithrombotic activity similar to that of heparin. But the in vivo efficacy is not just based on their anticoagulant activity. Their profibrinolytic actions and their strong TFPI-releasing effect may considerably contribute to this overall effect. Due to their manifold interactions with the system of hemostasis, each glucan sulfate shows a structure-dependent, individual action profile. From the investigated glucan sulfates, mainly C2- and C4-sulfated, linear beta-1,3-glucan sulfates with DS > 1.0 and MW between 18 and 50 kDa proved to be most suitable for a potential use as heparin alternatives. The results of this study demonstrate the impact of the various structural parameters on the antithrombotic activity of sulfated polysaccharides. However, the biological actions of sulfated polysaccharides are not limited to hemostasis, but they also show manifold modulating effects on other biological systems. Therefore, the approach of using highly sophisticated carbohydrate drug design might be a possibility to obtain new drugs with specific action profiles.
Alban
S
S
Institute of Pharmacy, University of Regensburg, Universitätsstrasse 31, 93040 Regensburg, Germany. Susanne.Alban@chemmie.uni-regensburg.de
Franz
G
G
D000818:Animals; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005936:Glucans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D013329:Structure-Activity Relationship; D013431:Sulfates / Q000737:chemistry*; D013552:Swine; D013917:Thrombin / Q000037:antagonists & inhibitors
D005343:Fibrinolytic Agents; D005936:Glucans; D013431:Sulfates; D013917:Thrombin