Importance of a 3-O-sulfate group in a heparin pentasaccharide for antithrombotic activity.
Previous theoretical and experimental evidence led to the formulation of a specific pentasaccharide structure which represents the site in heparin for binding to antithrombin III. This pentasaccharide was subsequently synthesized. A pentasaccharide of the same structure but lacking only the sulfate group on the hydroxyl group of the middle glucosamine (position C-3) was also synthesized to test the structure - activity relationships. Previous biochemical studies showed the 3-O-desulfated pentasaccharide to have a low affinity binding to AT III and to be devoid of the high anti-factor Xa activity characteristic of the pentasaccharide. Our in vivo studies, in a venous stasis thrombosis model proved the 3-O-desulfated pentasaccharide, at equigravimetric dosages, to be devoid of the antithrombotic activity previously reported for the pentasaccharide. These studies confirm the fact that inhibition of factor Xa at a high level of activity produces an antithrombotic effect.
Walenga
J M
JM
Loyola University Medical Center, Department of Pathology, Maywood, Illinois 60153.
Petitou
M
M
Samama
M
M
Fareed
J
J
Choay
J
J
D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D005343:Fibrinolytic Agents; D006493:Heparin; D008297:Male; D009844:Oligosaccharides; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D011817:Rabbits; D013431:Sulfates; D013918:Thrombin Time
D005343:Fibrinolytic Agents; D009844:Oligosaccharides; D013431:Sulfates; C049714:IC 831423; D006493:Heparin