A Synthetic Antithrombin III Binding Pentasaccharide Is Now a Drug! What Comes Next?

Abstract

Heparin is a sulfated glycosaminoglycan isolated from animal organs that has been used clinically as an antithrombotic agent since the 1940s. In the early 1980s it was discovered that a unique pentasaccharide domain in some heparin chains activates antithrombin III (AT-III), a serine protease inhibitor that blocks thrombin and factor Xa in the coagulation cascade. Sanofi-Synthélabo and Organon developed a synthetic analogue of this pentasaccharide. The resulting antithrombotic drug arixtra, which went on the market in the USA and Europe in 2002, shows superior antithrombotic activity and brings about AT-III-mediated activity against factor Xa exclusively. Structure-based design has subsequently led to analogues with longer-lasting activity, such as idraparinux, as well as novel conjugates and long oligosaccharides with specific anti-Xa and antithrombin activities. The new drug candidates are more selective in their mode of action than heparin and less likely to induce thrombocytopenia.

Molecular structure of basic oligomeric building units of heparan-sulfate glycosaminoglycans

“…Values of these glycosidic angles for individual dimers are considerably different (Table 1). Disaccharides investigated are part of the unique pentasaccharide-binding domain of heparin (also called the antithrombin III-binding domain), which is necessary to stimulate antithrombin activity [11]. The experimental values for the glycosidic angles in the pentasaccharideantithrombin complex are well interpreted by the corresponding angles computed for isolated dimeric structural units ( Table 1).…”

“…This complex organic acid, which is found especially in lung and liver tissue, has a mucopolysaccharide as its active constituent, prevents platelet agglutination and blood clotting, and is therapeutically used in the form of its sodium salt in the treatment of thrombosis and in heart surgery. Its antithrombotic activity is explained by the interaction with protein antithrombin III (AT-III) [7,[9][10][11]. The action of heparin starts when it binds to antithrombin through a group of five subunits (DEFGH).…”

“…It contains five O-sulfate groups, three N-sulfate groups, and two carboxylate moieties. In the antithrombin-pentasaccharide complex, these acidic groups are completely ionized and interact with the complementary amino acid side chains (Arg, Lys, Glu, and Asn) on the protein [11][12][13][14][15]. Despite its importance, the 3D molecular structure of native heparin and its simpler derivatives are not known.…”

Monitoring of heparin and its low-molecular-weight analogs by silicon field effect

“…Fondaparinux is therefore used for the prevention of thromboembolic events after elective orthopedic surgery and other prophylactic indications and for the treatment of deep venous thromboembolysms, pulmonary embolisms, and coronary artery diseases (16). Although LMWHs and fondaparinux improve on heparin's therapeutic limitations, they also have shortcomings.…”

A Facile Method for Oxidation of Primary Alcohols to Carboxylic Acids and Its Application in Glycosaminoglycan Syntheses

“…[4] With the recognition of their biological importance, chemical syntheses of GAGs are undergoing extensive studies; [2,5] such syntheses are typically carried out following two general approaches. In the first method, protected pyranosyl uronic acids are directly utilized.…”