Publikationsserver der Universitätsbibliothek Marburg
Titel:Synthese und Charakterisierung von Inhibitoren der hämagglutininspaltenden Proteasen Furin und HAT
Autor:Sielaff, Frank
Weitere Beteiligte: Steinmetzer, Torsten (Prof. Dr. )
Veröffentlicht:2011
URI:https://archiv.ub.uni-marburg.de/diss/z2011/0785
URN: urn:nbn:de:hebis:04-z2011-07855
DOI: https://doi.org/10.17192/z2011.0785
DDC: Naturwissenschaften
Titel (trans.):Synthesis and characterization of the haemagglutinin-cleaving proteases furin and HAT
Publikationsdatum:2011-12-19
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
influenza, inhibitor, Influenza-A-Virus, furin, Furin, flu, Grippe, Enzyminhibitor, HAT, HAT, Inhibitor, Vogelgrippe, Serinprotease

Zusammenfassung:
In der vorliegenden Arbeit wurden Inhibitoren der hämagglutininspaltenden Proteasen Furin und HAT synthetisiert und charakterisiert. Während die Proproteinkonvertase Furin das Hämagglutinin (HA) hochpathogener Influenzaviren vom Subtyp H5 und H7 aktiviert, bewirkt die trypsinartige Serinprotease HAT die Spaltung des HA saisonaler Influenzaviren der Subtypen H1, H2 und H3. Die entwickelten Hemmstoffe dieser Proteasen können somit als Ausgangsstoffe für die Entwicklung neuer antiviraler Wirkstoffe zur Therapie der Influenza dienen. Ein Bis-Amidinohydrazonderivat wurde in einem screening als Startpunkt für die Entwicklung neuer niedermolekularer Furininhibitoren identifiziert. In vier Syntheseserien wurden Furininhibitoren dieses Typs dargestellt. In der ersten Serie wurden kommerziell erhältliche Carbonylverbindungen als Ausgangsmaterial verwendet. Die wirksamste Verbindung dieser Serie mit einem Ki-Wert von 1,5 µM ist der vom Terephthalaldehyd abgeleitete Inhibitor. In zwei weiteren Serien wurden Derivate mit drei oder vier basischen Funktionen synthetisiert. Die Kopplung von 4 Guanidinobuttersäure an die Leitstruktur MI-0007 in der zweiten Serie und die Darstellung tetrabasischer Verbindungen unter Verwendung von in der dritten Serie führten zu Inhibitoren mit Hemmkonstanten von 0,5 - 0,6 µM. Ein aus der Literatur bekanntes, vom Salicylaldehydbenzylether abgeleitetes, monovalentes Amidinohydrazon mit einem Ki-Wert von 11,8 µM wurde als Leitstruktur einer vierten Serie von Furininhibitoren genutzt. Jedoch waren die Verbindungen dieser Serie weniger wirksam als die entsprechende aus der Literatur bekannte Ausgangsverbindung. Mit Ausnahme einer Verbindung, weisen alle im Rahmen dieser Arbeit synthetisierten Amidinohydrazonderivate eine hohe Selektivität gegenüber den untersuchten trypsinartigen Serinproteasen Thrombin, Faktor Xa und Plasmin auf (Ki-Werte > 30 µM). Für die trypsinartige Serinprotease HAT wurden bisher nur wenige Inhibitoren in der Literatur beschrieben. Deshalb begannen die Arbeiten zur Entwicklung der HAT-Inhibitoren mit einer Testung von im Arbeitskreis verfügbaren Verbindungen. Neben substratanalogen Inhibitoren mit einem C terminalen 4-Amidinobenzylamid konnten Verbindungen mit einem zentralen 3-Amidinophenylalanin des 3-TAPAP-Typs als Startpunkte für die Entwicklung von HAT-Hemmstoffen identifiziert werden. In sämtliche substratanaloge Inhibitoren wurde in P4- ein Benzylsulfonylrest und in P1-Position ein 4-Amidinobenzylamid eingebaut. In einer ersten Serie mit einem Prolin als P2-Rest wurden in P3 Position verschiedene D-Aminosäurereste akzeptiert, besonders jedoch das basische D-Arginin oder D-homo-Arginin. Akzeptiert werden auch hydrophobe Aminosäurederivate, wie ein tert.-butyl-geschütztes D-Asp oder D-Glu (Ki < 40 nM). Aufgrund der Präferenz für basische und hydrophobe Aminosäurereste in P3-Position, wurden in einer zweiten Serie die Seitenketten von D-Asp und D-Glu mit verschiedenen zyklischen Aminen modifiziert. Die wirksamste Verbindung wurde durch Kopplung von 1-(2-Pyrimidyl)piperazin an die Seitenkette von D-Glu erhalten und hemmt HAT mit einem Ki-Wert von 17 nM. Da substratanaloge Inhibitoren mit einem P2-Prolin häufig auch andere trypsinartige Serinproteasen hemmen, wurde der Einfluss anderer Aminosäuren in P2-Position in Kombination mit D-Arginin als P3-Rest untersucht. Die stärkste Hemmwirkung innerhalb dieser Serie mit Ki Werten < 30 nM wurde für kleine hydrophobe Aminosäurereste, wie 2-Aminobuttersäure (Abu), Norvalin (Nva), Valin oder Alanin gefunden. Ein Vorteil der Derivate mit Abu oder Nva in P2-Position ist deren verbesserte Selektivität gegenüber den Proteasen Thrombin, Faktor Xa und Plasmin. Die Verbindung Bzls-D-Arg-Nva-4-Amidinobenzylamid ist mit einer Hemmkonstante von 15 nM der erste Inhibitor, der die anderen getesteten Proteasen schwächer hemmt und somit die höchste Selektivität für HAT aufweist. Ausgewählte substratanaloge Inhibitoren wurden in Zellkulturversuchen eingesetzt, um die Hemmung der Vermehrung von Influenzaviren zu untersuchen. Eine besonders starke Hemmwirkung auf Influenzaviren der Subtypen H1 und H3 wurde durch Inhibitoren mit Norvalin oder 2-Aminobuttersäure in P2-Position bestimmt. Die Inhibitoren weisen darüber hinaus keine signifikante Zytotoxizität auf, so dass die reduzierte Virusausbreitung auf die HAT-Hemmung zurückzuführen ist. In der vorliegenden Arbeit wurden zahlreiche substratanaloge Inhibitoren identifiziert, die HAT mit Ki-Werten < 30 nM hemmen. Im Gegensatz zu den bereits etablierten antiviralen Wirkstoffen hemmen alle im Rahmen dieser Arbeit entwickelten Furin- und HAT-Inhibitoren Zielstrukturen des Wirts. Deshalb sollten auch bei längerer Verwendung dieser Verbindungen keine Resistenzen auftreten.

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