Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.5 (thrombin)
 33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Investigations identified peptide, platelet-selective thrombin inhibitors. Three peptides (MAP4-RPPGF, RGKWC and RGDWC) were relatively selective inhibitors of thrombin-induced platelet activation and calcium mobilization. MAP4-RPPGF at 35.5+/-0.03 microM inhibits gamma-thrombin-induced platelet aggregation 100% and alpha-thrombin-induced calcium mobilization in fibroblasts 84%. RGKWC at 800+/-400 microM inhibits gamma-thrombin-induced platelet aggregation 100% and calcium mobilization 63%. RGDWC at 140+/-100 microM inhibits gamma-thrombin-induced platelet aggregation 100% and calcium mobilization 32%. RGDWC also inhibits ADP-induced platelet aggregation, whereas MAP4-RPPGF and RGKWC do not. RGKWC prolongs the activated partial thromboplastin time (APTT) but not the prothrombin time (PT) or thrombin clotting time (TCT). RGKWC uniquely inhibits alpha-thrombin activation of human factor XI. Single amino acid substitutions in peptide pentamers result in differences in potency and mechanism(s) of inhibition of platelet and fibroblast activation by thrombin.
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PMID:Developing peptide inhibitors to thrombin activation of platelets from bradykinin analogs. 1175 56

Thrombostatins are a group of compounds based upon a breakdown product of bradykinin, RPPGF. They inhibit alpha-thrombin-induced platelet activation by binding to protease activated receptor 1 and, at a lower affinity, by interacting with thrombin's active site. After a single intravenous infusion of MAP4-RPPGF (11.58 mg/kg), its t1/2alpha was 4.5 min with a clearance of 2.0 ml/min. MAP4-RPPGF administration had a sustained antiplatelet effect, preventing gamma-thrombin-induced (12.5 nM) platelet activation for 4 h. Its antiplatelet effect summated with that of aspirin and/or clopidogrel. MAP4-RPPGF was compared with aspirin and clopidogrel in the Folts model of coronary artery thrombosis. Dogs were randomized to 3 treatment groups: aspirin 1.14 mg/kg i.v., clopidogrel 0.5 mg/kg i.v., or MAP4-RPPGF 0.77 mg/kg i.v. Cyclic flow variations (CFV) were recorded in 5 untreated dogs hourly for 3 successive hours and for 1 h before (all groups >11 CFV/h), and for 2 h after drug infusion in each of the 3 treatment groups. After 1 h drug treatment, all groups of animals had <6 CFV/h; after 2 h treatment, all had <1 CFV/h. All agents significantly reduced CFV from control at each hour, but none was significantly better than any other. Thrombostatin was as effective as aspirin or clopidogrel in inhibiting coronary artery thrombosis in this canine model.
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PMID:Thrombostatin inhibits cyclic flow variations in stenosed canine coronary arteries. 1181 21

Thrombin and protease-activated receptor 1 (PAR1) activation antagonists were prepared based upon the peptide RPPGF, the angiotensin-converting enzyme breakdown product of bradykinin. A library of 72 peptides consisting of d and/or synthetic amino acids was designed with various substitutions in positions 1 to 5 in Arg-Pro-Pro-Gly-Phe (RPPGF). Two compounds, rOicPGF (TH146) and betaAK2K-4(rOicPGF) (MAP4-TH146), were characterized further. TH146 or MAP4-TH146 completely inhibits threshold gamma-thrombin-induced platelet aggregation at a concentration of 142 +/- 0.05 or 19 +/- 0.06 microM, respectively. TH146 completely inhibits threshold alpha-thrombin-induced washed platelet aggregation at 444 +/- 0.04 microM. TH146 or MAP4-TH146 blocks 2 nM alpha-thrombin-induced fibroblast calcium mobilization with an IC(50) value of 110 or 18 microM, respectively. Furthermore, significant prolongation of the activated partial thromboplastin time, prothrombin time, or thrombin clotting time occurs at 31, 62, or 7.8 microM TH146 and 0.4, 6.25, or 1.56 microM MAP4-TH146, respectively. TH146 and MAP4-TH146 inhibit both alpha-thrombin with a K(i) value of 97 and 49 microM, respectively, and factor VIIa with a K(i) value of 44 and 5 microM, respectively. Both TH146 and MAP4-TH146 specifically bind to the exodomain of recombinant PAR1. MAP4-TH146 (200 microM) completely blocks thrombocytin, a PAR1-activating snake venom protease, without inhibiting the enzyme's active site. TH146 inhibits gamma-thrombin-induced aggregation of mouse platelets, prolongs mouse bleeding times, and delays the time to mouse carotid artery thrombosis. TH146 and MAP4-TH146 inhibit human and mouse platelet aggregation and mouse thrombosis. Analogs of RPPGF are model compounds to develop PAR1 activation antagonists as well as direct inhibitors to thrombin and factor VIIa.
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PMID:The preparation and characterization of novel peptide antagonists to thrombin and factor VIIa and activation of protease-activated receptor 1. 1521 Aug 36