Synthetic Heparin Pentasaccharide Depolymerization by Heparinase 1: Molecular and Biological Implications

A synthetic pentasaccharide (SR90107/ ORG31540) representing the antithrombin III (ATIII) binding sequence in heparin is under clinical development for the prophylaxis and management of venous thromboembolism. This pentasaccharide exhibits potent anti-factor Xa (AXa) effects (>750 lU/mg> and does not exhibit any anti-factor IIa (AIIa) activity. Previous reports have suggested that synthetic heparin pentasaccharides are resistant to the digestive effects of heparinase 1. To investigate the effect of heparinase I on the AXa activity of pentasaccharide SR90107/ORG31540. graded concentrations (1.25-100 μg/ml) were incubated with a fixed amount of heparinase I (0.1 U/ml). Heparinase I produced a strong neutralizing effect on this pentasaccharide, as measured by AXa activity. This observation led to further studies where high performance liquid chromatography (HPLC) analysis was eniployed to determine the potential breakdown products of the pentasaccharide. The experiment with the pentasaccharide included incub...