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001-es BibID:	BIBFORM033201
Első szerző:	Mendelboum Raviv, Shlomit (biológus)
Cím:	4-thio-deoxyuridylate modified thrombin aptamer and its inhibitory effect on fibrin clot formation, platelet aggregation and thrombus growrth on subendothelial matrix / S. Mendelboum Raviv, A. Horváth, J. Aradi, Z. Bagoly, F. Fazakas, Z. Batta, L. Muszbek, J. Hársfalvi
Dátum:	2008
ISSN:	1538-7933
Megjegyzések:	Background:?The consensus thrombin aptamer C15-mer is a single-stranded DNA of 15 nucleotides [d(GGTTGGTGTGGTTGG)] that was identified by the selection of thrombin-binding molecules from a large combinatorial library of oligonucleotides. It is capable of inhibiting thrombin at nanomolar concentrations through binding to a specific region within thrombin exosite 1. As has been shown in our earlier studies, the 4-thio-deoxyuridylate (s4dU)-containing oligonucleotides have high affinity for a number of proteins, due to the reduced hydrophilic character of the modified oligonucleotide. Methods:?Three different analogs of the original thrombin-inhibiting sequence, in which some of the thymidylate residues were replaced by 4-thio-deoxyuridylates, were synthesized. The inhibitory effect of modified aptamers was tested on thrombin-catalyzed fibrin clot formation and fibrinopeptide A release from fibrinogen, thrombin-induced platelet aggregation/secretion, and the formation of thrombus on coverslips coated with human collagen type III, thrombin-treated fibrinogen or subendothelial matrix of human microvascular endothelial cells. Results:?As compared with the C15-mer, the analog with the sequence GG(s4dU)TGG(s4dU)G(s4dU)GGT(s4dU)GG (UC15-mer) showed a 2-fold increased inhibition of thrombin-catalyzed fibrin clot formation, fibrinopeptide A release, platelet aggregation and secretion in human plasma and thrombus formation on thrombin-treated fibrinogen surfaces under flow conditions. Concerning the inhibition of thrombin-induced fibrin formation from purified fibrinogen and activation of washed platelets, UC15-mer was 3-fold and twelve-fold more effective than C15-mer, respectively.Conclusion:?The replacement of four thymidylate residues in C15-mer by 4-thio-deoxyuridylate resulted in a new thrombin aptamer with increased anticoagulant and antithrombotic properties.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban 4-thio-deoxyuridylate aptamer platelets thrombin thrombin exosite thrombus
Megjelenés:	Journal Of Thrombosis And Haemostasis. - 6 : 10 (2008), p. 1764-1771. -
További szerzők:	Horváth András (1976-) (vegyész) Aradi János (1942-) (biokémikus, vegyész) Bagoly Zsuzsa (1978-) (orvos) Fazakas Ferenc (1969-) (molekuláris biológus) Batta Zoltán Muszbek László (1942-) (haematológus, kutató orvos) Hársfalvi Jolán (1949-) (klinikai biokémikus)
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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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001-es BibID:	bibEBI00018624
Első szerző:	Ulrichts, Hans
Cím:	A monoclonal antibody directed against human von Willebrand factor induces type 2B-like alterations / Ulrichts, H., Hársfalvi, J., Bene, L., Matkó, J., Vermylen, J., Ajzenberg, N., Baruch, D., Deckmyn, H., Tornai, I.
Dátum:	2004
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:	Journal of Thrombosis and Haemostasis. - 2 : 9 (2004), p. 1622-1628. -
További szerzők:	Hársfalvi Jolán (1949-) (klinikai biokémikus) Bene László (1963-) (biofizikus) Matkó János (1952-) (biológus) Vermylen, Jozef Ajzenberg, N. Baruch, D. Deckmyn, Hans Tornai István (1954-) (belgyógyász, gasztroenterológus)
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