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001-es BibID:BIBFORM010452
Első szerző:Szántó Tímea
Cím:Identification of a VWF peptide antagonist that blocks platelet adhesion under high shear conditions by selectively inhibiting the VWF-collagen interaction / Szanto, T., Vanhoorelbeke, K., Toth, G., Vandenbulcke, A., Toth, J., Noppe, W., Deckmyn, H., Harsfalvi, J.
Dátum:2009
ISSN:1538-7933 (Print)
Megjegyzések:Because the collagen-VWF-GPIb/IX/V axis plays an important role in thrombus formation, it represents a promising target for development of new antithrombotic agents. Objectives: We used phage display to identify potential small peptides that interfere with the VWF-collagen binding and might serve as lead products for the development of possible oral antithrombotic compounds. Methods: A random linear heptamer peptide library was used to select VWF-binding peptides. Results: We identified a phage clone, displaying the YDPWTPS sequence, further referred to as L7-phage, that bound to VWF in a specific and a dose-dependent manner. This L7-phage specifically inhibited the VWF-collagen interaction under both static and flow conditions. Epitope mapping using deletion mutants of VWF revealed that the L7-phage does not bind to the known collagen-binding A3 domain within VWF, but to the more carboxyterminal situated C domain. This inhibition was not due to steric hindrance of the A3 domain-collagen interaction by the L7-phage. Indeed, a tetrabranched multi-antigen peptide (MAP) presenting four copies of the peptide, but not the scrambled MAP, also inhibited VWF-collagen interaction under conditions of high shear stress at a concentration of 148 nmol L<sup>-1</sup>. Conclusions: Based on these results, we conclude that we have identified the first peptide antagonist that binds to the VWF C domain and by this specifically inhibits the VWF binding to collagen, suppressing platelet adhesion and aggregation under high shear conditions. As a consequence, this peptide and its future derivates are potentially interesting antithrombotic agents.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Antithrombotic therapy
Collagen
Peptide inhibitor
Phage display
Platelet adhesion
Von Willebrand factor
antithrombocytic agent
collagen
epitope
unclassified drug
von Willebrand factor
amino acid sequence
article
biopanning
carboxy terminal sequence
concentration response
controlled study
deletion mutant
drug mechanism
drug protein binding
drug screening
human
normal human
phage display
priority journal
protein binding
protein domain
protein protein interaction
shear stress
stereospecificity
thrombocyte adhesion
thrombocyte aggregation inhibition
Collagen
Dose-Response Relationship
Drug
Drug Design
Drug Evaluation
Preclinical
Epitope Mapping
Fibrinolytic Agents
Hemorheology
Humans
Oligopeptides
Peptide Library
Platelet Adhesiveness
Platelet Aggregation
Platelet Aggregation Inhibitors
Protein Binding
Stress
Mechanical
von Willebrand Factor
Megjelenés:Journal of Thrombosis and Haemostasis. - 7 : 10 (2009), p. 1680-1687. -
További szerzők:Vanhoorelbeke, Karen Tóth Gábor (Szeged) Vandenbulcke, A. Tóth Judit (1978-) (laboratóriumi szakorvos) Noppe, W. Deckmyn, Hans Hársfalvi Jolán (1949-) (klinikai biokémikus)
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