Synthetic Inhibitors of Fibrinolysis

Markwardt, Fritz

doi:10.1007/978-3-642-66863-0_15

Cited by 11 publications

(19 citation statements)

References 235 publications

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“…Okamoto et al [29] concluded that the major effect of the antifibrinolytic agents was to prevent activation of plasminogen by tissue activators, and that fibrinolytic activity by plasmin was only mildly inhibited. However, Markwardt [30] has pointed out that the effect of antifibrinolytics on activation is much weaker than the observed antifibrinolytic activity. Another explanation of antifibrinolytic activity is inhibition of fibrin degradation by plasmin [2,30].…”

Section: Discussionmentioning

confidence: 98%

“…However, Markwardt [30] has pointed out that the effect of antifibrinolytics on activation is much weaker than the observed antifibrinolytic activity. Another explanation of antifibrinolytic activity is inhibition of fibrin degradation by plasmin [2,30]. If antifibrinolytics prevent formation of a plasminogen-fibrin complex [2], then the localized activation of plasminogen proposed by Wiman and Collen [18] will be prevented.…”

Section: Discussionmentioning

confidence: 98%

“…Okamoto et al [29] and Markwardt [30] have summarized the results of screening a large number of antifibrinolytic agents. As can be seen in Table 3, antifibrinolytic activity of o-amino acids also correlates very well with ~5 0 values.…”

Section: Discussionmentioning

confidence: 99%

“…Whatever the antifibrinolytic mechanism is, it appears from the data in Table 3 that the same sites are involved as in our studies. Okamoto et al [29] and Markwardt [30] also noted that the most important parameter for activity appears to be the actual distance (about 0.7 nm) between the carboxyl and amino groups, rather than the number of carbon atoms in the chain. It seems unlikely that a better ligand than trans-4-(aminomethyl)cyclohexanecarboxylic acid will be found, if the amine-to-carboxyl distance is of overriding importance, since extrapolation of the sides of the curves in Fig.3 and 4 leads to an intersection at about 0.68 nm, the amine-to-carboxyl distance in this ligand.…”

Section: Discussionmentioning

confidence: 99%

“…Several investigators [32 -341 have reported the binding of plasminogen to aromatic amines and benzamidines, some of which have strong antifibrinolytic activity [30]. Holleman et al [32] have provided evidence that there is an independent binding site on plasminogen for lysine and p-aminobenzamidine by showing that lysine will not elute plasminogen from aminobenzamidine-Sepharose and vice versa.…”

Section: Discussionmentioning

confidence: 99%

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Studies on the Lysine-Binding Sites of Human Plasminogen. The Effect of Ligand Structure on the Binding of Lysine Analogs to Plasminogen

Winn

Hochschwender

et al. 1980

Eur J Biochem

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A method is described for measuring relative binding constants of lysine and analogs of lysine to plasminogen and plasminogen 'kringle' fragments. Plasminogen or kringle fragments adsorbed to lysine-Sepharose are eluted with increasing concentrations of lysine or other ligands, the concentration of ligand required to elute 50% of the protein being taken as a measure of the binding constant. The method is simple and is not dependent on monitoring conformational changes. We confirm earlier reports that the best ligands for the lysine binding sites of plasminogen are w-amino acids containing five or six carbons. We show further that both Glu-plasminogen (the native form with N-terminal glutamic acid) and Lys-plasminogen (a degraded form with N-terminal lysine), as well as the heavy chain fragments, kringle 4 and kringle 1 + 2 + 3, have very similar properties with regard to binding specificity for w-amino acids. For all species optimal binding is observed when the distance between the amino and carboxyl carbon is about 0.68 nm. The binding of ligands is decreased by the presence of polar atoms on the a and p positions of the carbon chain of amino acids.Arginine binds relatively weakly at the lysine site and there does not appear to be a separate arginine binding site in plasminogen.It has been known for over 20 years that amino acids such as 6-aminohexanoic acid have antifibrinolytic properties [l], one of which probably results from inhibition of the binding of plasminogen to fibrin [2]. Subsequent studies have shown that 6-aminohexanoic acid and lysine cause extensive conformational alterations in Glu-plasminogen [3,4] (and references in [4]); Deutsch and Mertz [5] utilized the strong affinity of plasminogen for lysine-Sepharose in the development of a convenient method for purification of plasminogen.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Studies on the Lysine-Binding Sites of Human Plasminogen. The Effect of Ligand Structure on the Binding of Lysine Analogs to Plasminogen

Winn

Hochschwender

et al. 1980

Eur J Biochem

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Comparison of structure, strength and cytocompatibility of a fibrin matrix supplemented either with tranexamic acid or aprotinin

2007

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Fibrin sealants are used as hemostats, sealants, tissue adhesives, and as matrix for substances/cells in a number of surgical and tissue engineering procedures. Main characteristics of fibrin are high tensile strength, adhesive strength, biocompatibility, and resorption. A major adverse event would be premature fibrin lysis and recurrent bleeding. This must be prevented by fibrinolysis inhibitors. The most common fibrinolysis inhibitors used are aprotinin and tranexamic acid (t-AMCA). Comparison of commercially available fibrin sealants utilizing aprotinin or t-AMCA revealed a lower sealing efficacy in an in vivo lung resection model for a t-AMCA containing product. Therefore, we compared the influence of t-AMCA and aprotinin on structure, mechanical properties, and cytocompatibility of a fibrin matrix. In our experiments, we found that substitution of aprotinin with t-AMCA reduced the tensile strength and formation of fibrin fibers and affected viability of a fibroblast cell-line. In conclusion, t-AMCA negatively affects physical and biological properties of fibrin relevant for clinical application as well as tissue regeneration.

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Recent Advances on Plasmin Inhibitors for the Treatment of Fibrinolysis‐Related Disorders

Al‐Horani

Desai

2014

Medicinal Research Reviews

101

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Growing evidence suggests that plasmin is involved in a number of physiological processes in addition to its key role in fibrin cleavage. Plasmin inhibition is critical in preventing adverse consequences arising from plasmin overactivity, e.g., blood loss that may follow cardiac surgery. Aprotinin was widely used as an antifibrinolytic drug before its discontinuation in 2008. Tranexamic acid and ε-aminocaproic acid, two small molecule plasmin inhibitors, are currently used in the clinic. Several molecules have been designed utilizing covalent, but reversible, chemistry relying on reactive cyclohexanones, nitrile warheads, and reactive aldehyde peptidomimetics. Other major classes of plasmin inhibitors include the cyclic peptidomimetics and polypeptides of the Kunitz and Kazal-type. Allosteric inhibitors of plasmin have also been designed including small molecule lysine analogs that bind to plasmin's kringle domain(s) and sulfated glycosaminoglycan mimetics that bind to plasmin's catalytic domain. Plasmin inhibitors have also been explored for resolving other disease states including cell metastasis, cell proliferation, angiogenesis, and embryo implantation. This review highlights functional and structural aspects of plasmin inhibitors with the goal of advancing their design.

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Synthetic Inhibitors of Fibrinolysis

Cited by 11 publications

References 235 publications

Studies on the Lysine-Binding Sites of Human Plasminogen. The Effect of Ligand Structure on the Binding of Lysine Analogs to Plasminogen

Studies on the Lysine-Binding Sites of Human Plasminogen. The Effect of Ligand Structure on the Binding of Lysine Analogs to Plasminogen

Comparison of structure, strength and cytocompatibility of a fibrin matrix supplemented either with tranexamic acid or aprotinin

Recent Advances on Plasmin Inhibitors for the Treatment of Fibrinolysis‐Related Disorders

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