title: Ecotin: Exploring a feasible antithrombotic profile.
abstract: Ecotin is an Escherichia coli-derived protein that can inhibit serine proteases. It has been suggested that this protein (ecotin-WT) and some of its variants could be used to develop a prototype to treat thrombosis. In this work, the effect of ecotin-WT and a variant of this protein harboring two mutations (Met84Arg and Met85Arg, ecotin-RR) were analyzed to determine their ability to prevent thrombus formation using in vivo models. Ecotins were analyzed in vitro using the coagulation tests. An in vivo venous thrombosis rat model and a pulmonary thromboembolism mouse model were used to investigate the antithrombotic activity. The bleeding time in rats using a tail-transection model was evaluated as a possible side effect caused by the administration of these proteins. Ecotin-RR was more effective in inhibiting thrombin than ecotin-WT. Both ecotins presented similar mechanisms of anticoagulation activity and were able to decrease thrombus formation. In contrast, only ecotin-RR increased survival rates in the in vivo pulmonary thromboembolism model, reinforcing the antithrombotic activity of ecotin-RR. Ecotin-WT and more so ecotin-RR showed potent antithrombotic effects, not associated with bleeding. The presented results indicate that ecotin-WT and ecotin-RR may be new scaffolds that could be used to develop anticoagulation molecules.
authors.affiliation: Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia/CCS, Universidade Federal do Rio de Janeiro, Rio do Janeiro, RJ, Brazil; Instituto de Bioquímica Médica Leopoldo de Meis/CCS, Universidade Federal do Rio de Janeiro, Rio do Janeiro, RJ, Brazil. Electronic address: lwserrao@pharma.ufrj.br.
authors.forename: Luciana Serrão
authors.initials: LS
authors.lastname: Wermelinger
authors.affiliation: Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia/CCS, Universidade Federal do Rio de Janeiro, Rio do Janeiro, RJ, Brazil; Instituto de Bioquímica Médica Leopoldo de Meis/CCS, Universidade Federal do Rio de Janeiro, Rio do Janeiro, RJ, Brazil. Electronic address: flaviafrattani@pharma.ufrj.br.
authors.forename: Flávia Serra
authors.initials: FS
authors.lastname: Frattani
authors.affiliation: Instituto de Bioquímica Médica Leopoldo de Meis/CCS, Universidade Federal do Rio de Janeiro, Rio do Janeiro, RJ, Brazil. Electronic address: tatty.lobo@gmail.com.
authors.forename: Tatiana Correa
authors.initials: TC
authors.lastname: Carneiro-Lobo
authors.affiliation: California Institute of Quantitative Biosciences (QB3), University of California, San Francisco, San Francisco, CA, USA. Electronic address: charles.craik@ucsf.edu.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Craik
authors.affiliation: Laboratório de Antibióticos, Bioquímica e Modelagem Molecular (LABioMol), Departamento de Biologia Celular e Molecular, IB-/CEG, Universidade Federal Fluminense, Niterói, RJ, Brazil. Electronic address: hcastrorangel@vm.uff.br.
authors.forename: Helena Carla
authors.initials: HC
authors.lastname: Castro
authors.affiliation: Instituto de Bioquímica Médica Leopoldo de Meis/CCS, Universidade Federal do Rio de Janeiro, Rio do Janeiro, RJ, Brazil. Electronic address: lzingali@bioqmed.ufrj.br.
authors.forename: Russolina Benedeta
authors.initials: RB
authors.lastname: Zingali
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000737:chemistry / Q000494:pharmacology; D004195:Disease Models, Animal; D004789:Enzyme Activation; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000494:pharmacology*; D005260:Female; D005343:Fibrinolytic Agents / Q000737:chemistry* / Q000494:pharmacology*; D006470:Hemorrhage / Q000188:drug therapy; D006801:Humans; D008297:Male; D051379:Mice; D033903:Periplasmic Proteins / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D057057:Serine Proteases / Q000378:metabolism; D013923:Thromboembolism / Q000097:blood / Q000188:drug therapy
chemical_list: D000925:Anticoagulants; C039076:Eco protein, E coli; D029968:Escherichia coli Proteins; D005343:Fibrinolytic Agents; D033903:Periplasmic Proteins; D057057:Serine Proteases
keywords: Ecotin; Factor Xa inhibitor; Thrombin inhibitor