title: 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 microM, 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 microM). Identification of these cysteine derivatives represents an opportunity to develop potent and specific TAFI inhibitors.
authors.affiliation: Divisions of Cardiovascular Research, and Discovery Chemistry, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Yee H
authors.initials: YH
authors.lastname: Do
authors.forename: Donetta S
authors.initials: DS
authors.lastname: Gifford-Moore
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Beight
authors.forename: Radhakrishnan
authors.initials: R
authors.lastname: Rathnachalam
authors.forename: Valentine J
authors.initials: VJ
authors.lastname: Klimkowski
authors.forename: Alan M
authors.initials: AM
authors.lastname: Warshawsky
authors.forename: Deshun
authors.initials: D
authors.lastname: Lu
mesh_terms: D025901:Carboxypeptidase B2 / Q000037:antagonists & inhibitors*; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005342:Fibrinolysis / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D009842:Oligopeptides / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D009842:Oligopeptides; C044514:glycyl-glycyl-cysteine; D025901:Carboxypeptidase B2; D003545:Cysteine