Effects on Molecular Conformation and Anticoagulant Activities of 1,6-Anhydrosugars at the Reducing Terminal of Antithrombin-Binding Octasaccharides Isolated from Low-Molecular-Weight Heparin Enoxaparin
2010; American Chemical Society; Volume: 53; Issue: 22 Linguagem: Inglês
10.1021/jm100771s
ISSN1520-4804
AutoresMarco Guerrini, Stefano Elli, Davide Gaudesi, Giangiacomo Torri, Benito Casu, Pierre Mourier, Fréderic Herman, Christian Boudier, M. Lorenz, Christian Viskov,
Tópico(s)Platelet Disorders and Treatments
ResumoTerminal 1,6-anhydro-aminosugars (1,6-anAS) are typical structural moieties of enoxaparin, a low-molecular-weight heparin (LMWH) widely used for prevention and treatment of thrombotic disorders. In the enoxaparin manufacturing process, these modified amino sugars are formed during the β-eliminative cleavage of heparin. To investigate the effect of terminal anAS on antithrombin (AT) binding and on inhibition of factor Xa (FXa), two octasaccharides containing modified AT-binding pentasaccharide sequences were isolated from enoxaparin. The molecular conformation of the octasaccharides terminating with N-sulfo-1,6-anhydro-d-mannosamine and N-sulfo-1,6-anhydro-d-glucosamine, respectively, has been determined both in the absence and presence of AT by NMR experiments and docking simulations. Reduced overall contacts of the terminal anAS residues with the binding region of AT induce a decrease in affinity for AT as well as lower anti-FXa activity. The anti-FXa measured either in buffer or plasma milieu does not show any significant difference, suggesting that the inhibition of anti-FXa remains specific and biologically relevant.
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