Inhibition of thrombin activatable fibrinolysis inhibitor by cysteine derivatives

Abstract

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 TAFI inhibitors containing a cysteine backbone. Three cysteine derivatives, guanidinyl- l-cysteine, glycyl- l-cysteine, and glycyl-glycyl- l-cysteine were tested in TAFI substrate assays and showed K app i=0.08, 0.14, and 0.99 μM, respectively. Subsequent fibrinolysis assays confirmed their TAFI inhibitory activities. Guanidinyl- l-cysteine showed inhibitory activity in a human plasma clot lysis assay (IC 50=9.4 μM). Identification of these cysteine derivatives represents an opportunity to develop potent and specific TAFI inhibitors.