Inhibition of Thrombin Activatable Fibrinolysis Inhibitor by cysteine derivatives

Thrombin Activatable Fibrinolysis Inhibitor (TAFI) is a basic carboxypeptidase that functions as a fibrinolysis inhibitor through the cleavage of C-terminal lysine on partially degraded fibrin. Modulation of TAFI activity provides a potential therapy for thrombosis complications by potentiating fibrinolysis. In our study, we identified three novel TAR inhibitors containing a cysteine backbone. Three cysteine derivatives, guanidinyl-L-cysteine, glycyl-L-cysteine, and glycyl-glycyl-L-cysteine were tested in TAR substrate assays and showed K-app(i) = 0.08, 0.14, and 0.99 mu M, respectively. Subsequent fibrinolysis assays confirmed their TAR inhibitory activities. Guanidinyl-L-cysteine showed inhibitory activity in a human plasma clot lysis assay (IC50 = 9.4 mu M). Identification of these cysteine derivatives represents an opportunity to develop potent and specific TAFI inhibitors. (c) 2005 Elsevier Ltd. All rights reserved.