Abstract:
INTRODUCTION:The A-subunit of blood coagulation factor XIII is a pro-transglutaminase, which cross-links α- and γ-fibrin-chains in its activated form. Selective inhibitors against FXIII-A may be desirable drugs to prevent the development of thromboses. Animal models are generally used for proof of principle and for toxicological studies in drug development. The aim of the study was to investigate the specificity of a set of FXIII-A-blockers against FXIII-A from different species, i.e. human, dog, mouse, rat and pig. Thus the usefulness of different animal species for FXIII-A-blocker drug development should be evaluated. MATERIALS AND METHODS:FXIII-A proteins were recombinantly produced in insect cells and purified to homogeneity. They were characterized by SDS- and native PAGE, a transamidase assay and isopeptidase assay. The inhibition second-order rate constants of different irreversible inhibitors were determined using the isopeptidase assay. RESULTS:All FXIII-A species were able to assemble with recombinant human FXIII-B into a heterotetrameric complex. Kinetic parameters of FXIII-A species were determined. Second-order rate constants for FXIII-A inhibition by two irreversible inhibitors were determined and differed considerably. FXIII-A species of dog, mouse and rat were inhibited in a manner similar to human FXIII-A. Pig FXIII-A however was resistant to a previously described non-peptidic inhibitor. Furthermore, the results showed considerably better inhibition with the novel peptide-based inhibitor compared to the non-peptidic compound. CONCLUSIONS:Our data shows that biochemical interspecies comparison studies are a prerequisite for animal studies. Peptide-derived inhibitors carrying a Michael Acceptor Pharmacophore (MAP) are a promising new class of FXIII-A-inhibitors.
journal_name
Thromb Resjournal_title
Thrombosis researchauthors
Heil A,Weber J,Büchold C,Pasternack R,Hils Mdoi
10.1016/j.thromres.2013.02.008subject
Has Abstractpub_date
2013-05-01 00:00:00pages
e214-22issue
5eissn
0049-3848issn
1879-2472pii
S0049-3848(13)00052-2journal_volume
131pub_type
杂志文章abstract:BACKGROUND:Our goal is to develop a vascular targeting treatment for brain arteriovenous malformations (AVMs). Externalized phosphatidylserine has been established as a potential biomarker on the endothelium of irradiated AVM blood vessels. We hypothesize that phosphatidylserine could be selectively targeted after AVM ...
journal_title:Thrombosis research
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更新日期:1990-12-01 00:00:00
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更新日期:2011-10-01 00:00:00
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更新日期:2008-01-01 00:00:00
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更新日期:2016-04-01 00:00:00
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更新日期:1992-02-01 00:00:00
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doi:10.1016/0049-3848(87)90428-2
更新日期:1987-12-15 00:00:00
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更新日期:2016-07-01 00:00:00
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abstract::A validated method for assessing hemostasis in vivo is critical for testing the hemostatic efficacy of therapeutic agents in preclinical animal models and in patients with inherited bleeding disorders, such as von Willebrand disease (VWD) and hemophilia A, or with acquired bleeding disorders such as those resulting fr...
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pub_type: 杂志文章,多中心研究
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doi:10.1016/j.thromres.2012.11.014
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更新日期:2002-09-01 00:00:00
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更新日期:2016-04-01 00:00:00
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pub_type: 杂志文章
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更新日期:2010-03-01 00:00:00
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journal_title:Thrombosis research
pub_type: 杂志文章
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更新日期:1993-04-01 00:00:00
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更新日期:2010-06-01 00:00:00
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pub_type: 杂志文章
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更新日期:2002-04-15 00:00:00
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journal_title:Thrombosis research
pub_type: 杂志文章
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更新日期:2003-01-01 00:00:00