| Full text | |
| Author(s): |
Lourenco Oliveira, Daniella Gorete
[1]
;
Alvarez-Flores, Miryam Paola
[1, 2]
;
Lopes, Adriana Rios
[1]
;
Chudzinski-Tavassi, Ana Marisa
[1, 2]
Total Authors: 4
|
| Affiliation: | [1] Butantan Inst, Biochem & Biophys Lab, BR-05503900 Sao Paulo - Brazil
[2] Butantan Inst, Ctr Appl Toxinol CAT CEPID, BR-05503900 Sao Paulo - Brazil
Total Affiliations: 2
|
| Document type: | Journal article |
| Source: | THROMBOSIS AND HAEMOSTASIS; v. 108, n. 3, p. 570-578, SEP 2012. |
| Web of Science Citations: | 4 |
| Abstract | |
The strategic position of factor Xa (FXa) in blood coagulation makes it a compelling target for the development of new anticoagulants. Blood-sucking animals have in their salivary glands mixtures of anticoagulants, which could be used for designing novel antithrombotic compounds. Herein, we describe Vizottin, the first FXa inhibitor from the salivary complex of the leech Haementeria vizottoi. Vizottin was purified by gel filtration and reverse-phase chromatography, and shown to have anticoagulant effects in human plasma, prolonging the recalcification time in a dose-dependent manner (IC50 40 nM). Vizottin induced blood incoagulability in FX-deficient plasma, whereas in normal and reconstituted plasma, Vizottin doubled the prothrombin time at 160 nM. This peptide competitively inhibited human FXa (K-i 2 nM) like FXa inhibitors from other leeches, albeit via a distinct mechanism of action. At high concentrations, vizottin inhibited the amidolytic activity of factor VIIa/tissue factor (IC50 96.4 nM). Vizottin inhibited FXa in the prothrombinase complex and Gla-domainless FXa. Moreover, vizottin did not interfere with FX activation induced by RVV-X, a known enzyme that requires the Gla-domain of FX for activation. Competition experiments in the presence of FXa and GGACK-FXa (active site blocked) demonstrated that the inhibition of FXa by vizottin is through binding to the active site rather than an exosite. This novel inhibitor appears to exert its inhibitory effects through direct binding to the active site of FXa in a time-dependent manner, but not involving a tight-binding model. In this context, vizottin is a promising model for designing novel anticoagulants for the treatment of thrombotic diseases. (AU) | |
| FAPESP's process: | 98/14307-9 - Center for Applied Toxinology |
| Grantee: | Hugo Aguirre Armelin |
| Support Opportunities: | Research Grants - Research, Innovation and Dissemination Centers - RIDC |