Pharmacology

Lepirudin acts independently of the cofactors antithrombin and heparin cofactor II (Markwardt, 1992) and forms tight, noncovalent 1 : 1 complexes with thrombin. Interacting with both binding sites, lepirudin is a bivalent inhibitor of thrombin (Fig. 1). Lepirudin inhibits all the biological activities of thrombin.

Three amino acids (residues 46-48) near the NH2-terminus of hirudin bind to the active site cleft on thrombin, while the core of the hirudin molecule closes off the active site pocket of thrombin. The COOH-terminal tail of hirudin interacts with the fibrinogen anion-binding site, helping to block thrombin-catalyzed fibrinogen

FIGURE 1 Schematic representation of the thrombin molecule and its inhibition by hirudin, bivalirudin (formerly, Hirulog), hirugen, and argatroban: (1) active-site pocket; (2) fibrinogen-binding site. The active-site pocket catalyzes most of the functions of the thrombin molecule, whereas the fibrinogen-binding exosite mediates the binding of thrombin to fibrinogen. Hirudin is a 7000 Da (7kDa) protein composed of 65 amino acids, which binds to the active-site pocket and the fibrinogen-binding exosite of thrombin, i.e., it is a bivalent direct thrombin inhibitor. Bivalirudin is a small synthetic peptide (20 amino acids) designed also to block both of these sites on thrombin. Hirugen, a synthetic peptide, mimics the binding site of fibrinogen to thrombin, thereby inhibiting binding of thrombin to fibrinogen and, therefore, fibrinogen cleavage by thrombin. The arginine derivative argatroban binds competitively to only the active binding site pocket of thrombin. Hirugen and argatroban are univalent direct thrombin inhibitors. Source: Adapted from Hermann et al., 1997.

Bivalirudin Hirugen Argatroban

FIGURE 1 Schematic representation of the thrombin molecule and its inhibition by hirudin, bivalirudin (formerly, Hirulog), hirugen, and argatroban: (1) active-site pocket; (2) fibrinogen-binding site. The active-site pocket catalyzes most of the functions of the thrombin molecule, whereas the fibrinogen-binding exosite mediates the binding of thrombin to fibrinogen. Hirudin is a 7000 Da (7kDa) protein composed of 65 amino acids, which binds to the active-site pocket and the fibrinogen-binding exosite of thrombin, i.e., it is a bivalent direct thrombin inhibitor. Bivalirudin is a small synthetic peptide (20 amino acids) designed also to block both of these sites on thrombin. Hirugen, a synthetic peptide, mimics the binding site of fibrinogen to thrombin, thereby inhibiting binding of thrombin to fibrinogen and, therefore, fibrinogen cleavage by thrombin. The arginine derivative argatroban binds competitively to only the active binding site pocket of thrombin. Hirugen and argatroban are univalent direct thrombin inhibitors. Source: Adapted from Hermann et al., 1997.

cleavage. Hirudin inhibits the feedback loop whereby thrombin enhances its own generation via activation of factors Va and VIIIa (Kaiser and Markwardt, 1986; Pieters et al., 1989). In addition to inhibiting free thrombin, hirudin inhibits clot-bound thrombin (Hogg and Jackson, 1989; Weitz et al., 1990) and thrombin bound to fibrin split products (Weitz et al., 1998). In contrast, heparin-antithrombin complexes are unable to access and inactivate clot-bound thrombin. This important difference between hirudin and heparin might explain why hirudin is more effective than heparin in promoting dissolution of mural thrombi in experimental models (Meyer et al., 1998). Hirudin shows virtually no interaction with plasma proteins (Glusa and Markwardt, 1990), and its activity is standardized in thrombin inhibitory units (TIU): 1 TIU is the amount of hirudin inhibiting 1 U of thrombin at 37°C. The specific activity of lepirudin is 16,000 TIU/mg.

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