Document Detail

Molecular design and characterization of recombinant long half-life mutants of human tissue factor pathway inhibitor.
MedLine Citation:
PMID:  15968388     Owner:  NLM     Status:  MEDLINE    
Tissue factor pathway inhibitor (TFPI) is a physiological inhibitor of extrinsic pathway of coagulation and has biological functions of anticoagulation and anti-inflammation. Although TFPI has been proved to be a good therapeutic agent of sepsis, inflammatory shock, and DIC, the clinical application and therapeutic effects of TFPI are impeded because of its short half-life in vivo. In order to prolong the half-life of TFPI, homology modeling and molecule docking were performed on a computer workstation principally in protein structural biology and binding characteristics between TFPI and its receptor LRP (low-density lipoprotein receptor related protein). Two recombinant long half-life human TFPI mutants coined TFPI-Mut1 and TFPI-Mut4 were designed and expressed in E.coli. In comparison with the wild-type TFPI, TFPI-Mut1 and TFPI-Mut4 presented a few of changes in spatial configuration and a decrease in relative Gibbs free energy of docking complex by 17.3% and 21.5%, respectively, as indicated by a computer simulation. After refolding and purification, anticoagulant activities, anti-TF/FVIIa and anti-FXa activities of the mutants were found to be the same as those of wide-type TFPI. The pharmacokinetics research indicated that alpha phase half-life (t1/2 alpha) of TFPI-Mut1 and TFPI-Mut4 were prolonged 1.33-fold and 1.96-fold respectively, beta phase half-life (t1/2 beta) of TFPI-Mut1 and TFPI-Mut4 were prolonged 1.62-fold and 4.22-fold respectively. These results suggested that TFPI-Mut1 and TFPI-Mut4 maintained the bioactivities of wild-type TFPI, prolonged half-life in vivo simultaneously and were expected for better clinical value and therapeutic effect.
Hao Bai; Duan Ma; Yu-Gao Zhang; Nong Zhang; De-Sheng Kong; Hong-Shen Guo; Wei Mo; Qi-Qun Tang; Hou-Yan Song
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Thrombosis and haemostasis     Volume:  93     ISSN:  0340-6245     ISO Abbreviation:  Thromb. Haemost.     Publication Date:  2005 Jun 
Date Detail:
Created Date:  2005-06-21     Completed Date:  2005-09-23     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  7608063     Medline TA:  Thromb Haemost     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  1055-60     Citation Subset:  IM    
Key Laboratory of Molecular Medicine, Ministry of Education, Fudan University, 130 Dongan Rd, Shanghai 200032, China.
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MeSH Terms
Anticoagulants / chemistry,  metabolism,  pharmacology
Computer-Aided Design
Drug Design
LDL-Receptor Related Proteins / metabolism
Lipoproteins / chemistry*,  genetics*,  metabolism,  pharmacology
Protein Conformation
Protein Engineering
Rats, Sprague-Dawley
Recombinant Proteins / chemistry,  genetics,  metabolism,  pharmacology
Reg. No./Substance:
0/Anticoagulants; 0/LDL-Receptor Related Proteins; 0/Lipoproteins; 0/Recombinant Proteins; 0/lipoprotein-associated coagulation inhibitor

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