Hemmstoffe von Faktor XIIIa

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.

Schlüsselwörter

Faktor XIIIa - Hemmstoffe - kompetitive Substrate

Keywords

Factor XIIIa - inhibitors - competitive substrates

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