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DOI: 10.1055/s-0037-1622005
Hemmstoffe von Faktor XIIIa
Inhibitors of factor XIIIaPublikationsverlauf
Publikationsdatum:
29. Dezember 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00034925/200201/lookinside/thumbnails/10-1055-s-0037-1622005_de-1.jpg)
Zusammenfassung
Der Gerinnungsfaktor XIIIa (FXIIIa) stabilisiert die bei der Blutgerinnung entstehenden Fibringerinnsel und erhöht deren Widerstandsfähigkeit gegenüber Fibrinolyse. Darüber hinaus ist FXIIIa an anderen (patho)physiologischen Vorgängen, z. B. Wundheilung und Arteriosklerose, beteiligt. Für die Aufklärung der verschiedenen FXIIIa-Funktionen einschließlich ihrer pharmakologischen Beeinflussung könnten selektive Hemmstoffe ein wertvolles Hilfsmittel sein. Diese Arbeit gibt einen überblick über zurzeit bekannte Hemmstoffe von FXIIIa. Analoga der natürlichen FXIIIa-Substrate – dazu gehören glutaminhaltige Peptide und kleinmolekulare substituierte Alkylamine – werden als kompetitive Substrate in das Fibrinnetz eingebaut und verhindern die Quervernetzung. Natürliche, direkte Hemmstoffe von Faktor XIIIa wurden aus einer Blutegelspezies und verschiedenen Mikroorganismen isoliert. Der wirksamste bekannte Hemmstoff ist das Peptid Tridegin mit effektiven Konzentrationen im nanomolaren Bereich. Synthetische, kleinmolekulare Hemmstoffe binden meist kovalent an die SH-Gruppe von Cys314 im aktiven Zentrum von FXIIIa. Neben den relativ unspezifischen SH-Reagenzien wurden Azolderivate bzw. Azoliumsalze und verwandte Verbindungen als spezifische FXIIIa-Hemmstoffe beschrieben. Tierexperimentelle Untersuchungen zeigten, dass in Gegenwart eines FXIIIa-Hemmstoffs die Thrombolyse mit einem Plasminogenaktivator effektiver wird.
Summary
Factor XIIIa (FXIIIa) catalyzes the covalent crosslinking of fibrin polymers and incorporation of proteins into the fibrin network and thus confers on the thrombus additional structural stability and relative resistance to plasmin-mediated degradation. Moreover, FXIIIa is involved in other physiological and pathophysiological processes such as wound healing and arteriosclerosis. Selective FXIIIa inhibitors may be a valuable tool for evaluation of the various functions of FXIIIa and their pharmacological control. This paper presents an overview of the inhibitors of FXIIIa. Analogues of natural FXIIIa substrates – including glutamine containing peptides and low molecular weight substituted alkylamines – are incorporated into the fibrin network and thus prevent crosslinking of fibrin. Naturally occurring, direct inhibitors of FXIIIa have been isolated from a leech species and microorganisms. With effective concentrations in the nanomolar range the peptide tridegin is the most potent FXIIIa inhibitor up to now. The majority of the synthetic, low molecular weight inhibitors bind covalently to Cys314 at the active site of FXIIIa. Besides the relatively nonspecific thiol reagents, azol derivatives, azolium salts and related substances are described as specific inhibitors of FXIIIa. They inhibit the activity of FXIIIa at nanomolar concentrations. Animal experiments have demonstrated improved thrombolysis by a plasminogen activator in combination with a FXIIIa inhibitor.
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Literatur
- 1 Achyuthan KE, Slaughter TF, Santiago MA. et al Factor XIIIa-derived peptides inhibit transglutaminase activity. Localization of substrate recognition sites. J Biol Chem 1993; 268: 21284-92.
- 2 Atkinson JG, Baldwin JJ, Claremon DA. et al. Factor XIIIa inhibitor compounds useful for thrombolytic therapy. EP0294016 1988
- 3 Baldwin JJ, Remy DC, Claremon DA. Imidazole compounds and their use as transglutaminase inhibitors. US5030644 1991
- 4 Barry EL, Mosher DF. Factor XIII cross-linking of fibronectin at cellular matrix assembly sites. J Biol Chem 1988; 263: 10464-9.
- 5 Bruner-Lorand J, Pilkington TRE, Lorand L. Inhibitors of fibrin cross-linking: Relevance for thrombolysis. Nature 1966; 210: 1273-4.
- 6 Chen GT. Transglutaminase enzyme inhibitors. WO9213530 1992
- 7 Claremon DA, Baldwin JJ, Remy DC. Imidazole compounds and their use as transglutaminase inhibitors. US5084444 1992
- 8 Claremon DA, Remy DC, Baldwin JJ. Imidazole compounds and their use as transglutaminase inhibitors. US5077285 1991
- 9 Coyne CP, Smith JE, DeBowes RM. Pharmacologic evaluation of factor XIIIa*-like enzyme activity in equine plasma as a potential therapeutic avenue for the inhibition of fibrinous tissue. Am J Vet Res 1992; 53: 695-705.
- 10 Finney S, Seale L, Sawyer RT. et al Tridegin, a new peptidic inhibitor of factor XIIIa, from the bloodsucking leech Haementeria ghilianii. Biochem J 1997; 324: 797-805.
- 11 Freund KF, Doshi KP, Gaul SL. et al Transglutaminase inhibition by 2-[(2-oxopropyl) thio]imidazolium derivatives: mechanism of factor XIIIa inactivation. Biochemistry 1994; 33: 10109-19.
- 12 Freund KF, Gaul SL, Doshi KP. et al A novel factor XIII inhibitor enhances clot lysis rates. Fibrinolysis 1988; 2 Abstract 154.
- 13 Gorman JJ, Folk JE. Structural features of glutamine substrates for transglutaminases. Role of extended interactions in the specificity of human plasma factor XIIIa and of the guinea pig liver enzyme. J Biol Chem 1984; 259: 9007-10.
- 14 Henderson KW, Nussbaum M. Mechanism of enhanced streptokinase-induced clot lysis following in-vitro factor-XIII inactivation. Br J Haematol 1969; 17: 445-53.
- 15 Ikura K, Minami K, Otomo C. et al High molecular weight transglutaminase inhibitor produced by a microorganism (Streptomyces lavendulae Y-200). Biosci Biotechnol Biochem 2000; 64: 116-24.
- 16 Iwata Y, Tago K, Kiho T. et al Conformational analysis and docking study of potent factor XIIIa inhibitors having a cyclopropenone ring. J Mol Graph Model 2000; 18: 591-94.
- 17 Karpati L, Katona E, Rejto L. et al Elevated plasma factor XIII activity and concentration in patients with essential thrombocythemia or other myeloproliferative disorders. Thromb Haemost 2001; Suppl OC 2484.
- 18 Katona E, Nagy B, Kappelmayer J. et al Factor XIII in bronchoalveolar lavage fluid of children with chronic lung disorders. Thromb Haemost 2001; Suppl: P603.
- 19 Kimura S, Tamaki T, Aoki N. Acceleration of fibrinolysis by the N-terminal peptide of alpha 2-plasmin inhibitor. Blood 1985; 66: 157-60.
- 20 Kloczko J, Wojtukiewicz M, Bielawiec M. et al Plasma factor XIII and some other haemostasis parameters in patients with diabetic angiopathy. Acta Haematol 1986; 73: 81-5.
- 21 Kloczko J, Wojtukiewicz M, Bielawiec M. et al Alterations of haemostasis parameters with special reference to fibrin stabilization, factor XIII and fibronectin in patients with obliterative atherosclerosis. Thromb Res 1988; 51: 575-81.
- 22 Kogen H, Kiho T, Tago K. et al Alutacenoic acids A and B, rare naturally occuring cyclopropenone derivatives isolated from fungi: potent non-peptide factor XIIIa inhibitors. J Am Chem Soc 2000; 122: 1842-3.
- 23 Kontoyianni M, Teller DC, Yee VC. Methods for inhibiting factor XIII activity. WO9702340 2001
- 24 Lee KN, Fesus L, Yancey ST. et al Development of selective inhibitors of transglutaminase. Phenylthiourea derivatives. J Biol Chem 1985; 260: 14689-94.
- 25 Lee SY, Chang SK, Lee IH. et al Depletion of plasma factor XIII prevents disseminated intravascular coagulation-induced organ damage. Thromb Haemost 2001; 85: 464-9.
- 26 Leidy EM, Stern AM, Friedman PA. et al Enhanced thrombolysis by a factor XIIIa inhibitor in a rabbit model of femoral artery thrombosis. Thromb Res 1990; 59: 15-26.
- 27 Lorand L. Sol Sherry Lecture in thrombosis – Research on clot stabilization provides clues for improving thrombolytic therapies. Arterioscler Thromb Vasc Biol 2000; 20: 2-9.
- 28 Lorand L, Konishi K, Jacobsen A. Transpeptidation mechanism in blood clotting. Nature 1962; 194: 1148-9.
- 29 Lorand L, Parameswaran KN, Velasco PT. et al Biotinylated peptides containing a factor XIIIa or a tissue transglutaminase-reactive glutaminyl residue that block protein cross-linking phenomena by becoming incorporated into amine donor sites. Bioconjug Chem 1992; 3: 7-41.
- 30 Lorand L, Rule NG, Ong HH. et al. Amine specificity in transpeptidation. Inhibition of fibrin crosslinking. Biochemistry 1968; 7: 1214-23.
- 31 Marktl W, Rudas B. The effect of factor XIII on wound granulation in the rat. Thromb Diath Haemorrh 1974; 32: 578-81.
- 32 Nilsson JLG, Stenberg P, Ljunggren C. et al. Fibrin-stabilizing factor inhibitors. Ann NY Acad Sci 1972; 202: 286-96.
- 33 Parameswaran KN, Velasco PT, Wilson J. et al Labeling of epsilon-lysine cross-linking sites in proteins with peptide substrates of factor XIIIa and transglutaminase. Proc Natl Acad Sci USA 1990; 87: 8472-5.
- 34 Pola P, Dallago A, Flore R. et al. Pharmacologic reduction of factor XIII activity and fibrinogenemia in patients with peripheral arterial occlusive disease. Curr Ther Res 1998; 59: 389-94.
- 35 Pola P, Savi L. Inhibition of factor XIII as a preventive and therapeutic possibility in atherosclerosis. Minerva Cardioangiol 1977; 25: 643-6.
- 36 Pötzsch B. Faktor XIII: Biochemie, Molekularbiologie und Physiologie. In: Hämostaseologie. Müller-Berghaus G, Pötzsch B. (Hrsg) Berlin, Heidelberg: Springer Verlag; 1998: 291-8.
- 37 Reed GL, Houng AK. The contribution of activated factor XIII to fibrinolytic resistance in experimental pulmonary embolism. Circulation 1999; 99: 299-304.
- 38 Reinhardt G. Alpha-Halogenmethyl carbonyl compounds as very potent inhibitors of factor XIIIa in vitro. Ann NY Acad Sci 1981; 370: 836-42.
- 39 Remy DC, Baldwin JJ, Claremon DA. et al. Triazole compounds and their use as transglutaminase inhibitors. US5047416 1991
- 40 Remy DC, Baldwin JJ, Claremon DA. et al Medicinal use of certain tetrazolium salts. US5177092 1993
- 41 Sawyer RT, Wallis RB, Seale L. et al Inhibitors of fibrin crosslinking and/or transglutaminases. US6025330 1998
- 42 Seale L, Finney S, Sawyer RT. et al. Tridegin, a novel peptidic inhibitor of factor XIIIa from the leech, Haementeria ghilianii, enhances fibrinolysis in vitro. Thromb Haemost 1997; 77: 959-63.
- 43 Shebuski RJ, Sitko GR, Claremon DA. et al Inhibition of factor XIIIa in a canine model of coronary thrombosis: effect on reperfusion and acute reocclusion after recombinant tissue-type plasminogen activator. Blood 2000; 75: 1455-9.
- 44 Song YC, Sheng D, Taubenfeld SM. et al. A microtiter assay for factor XIII using fibrinogen and biotinylcadaverine as substrates. Anal Biochem 1994; 223: 88-92.
- 45 Takahashi H, Isobe T, Horibe S. et al. Tissue transglutaminase, coagulation factor XIII, and the propolypeptide of von Willebrand factor are all ligands for the integrins alpha 9beta 1 and alpha 4beta 1. J Biol Chem 2000; 275: 23589-95.
- 46 Tymiak AA, Tuttle JG, Kimball SD. et al. A simple and rapid screen for inhibitors of factor XIIIa. J Antibiot 1993; 46: 204-6.
- 47 Ueki S, Takagi J, Saito Y. Dual function of transglutaminase in novel cell adhesion. J Cell Sci 1996; 109: 2727-35.
- 48 West RR, Martinez T, Franklin HR. et al. Factor XIIIa inhibitor. US5710174 2001
- 49 Yamada T, Yoshiyama Y, Kawaguchi N. et al. Possible roles of transglutaminases in Alzheimer’s disease. Dement Geriatr Cogn Disord 1998; 9: 103-10.