Publikationsserver der Universitätsbibliothek Marburg
Titel:Carbonic Anhydrase II: A Model System for Artificial Copper Center Design, Protein-guided Cycloadditions, Tethering Screenings and Fragment-based Lead Discovery
Autor:Schulze Wischeler, Johannes
Weitere Beteiligte: Klebe, Gerhard (Prof. Dr.)
Veröffentlicht:2010
URI:https://archiv.ub.uni-marburg.de/diss/z2010/0356
DOI: https://doi.org/10.17192/z2010.0356
URN: urn:nbn:de:hebis:04-z2010-03568
DDC: Naturwissenschaften
Titel (trans.):Carboanhydrase II: Ein Modellsystem für das Design eines künstlichen Cu-Zentrums, Protein-gelenkte Cycloadditionen, Tethering Screenings und Fragment-basierte Leitstruktursurche
Publikationsdatum:2010-07-08
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Click-Chemie, Wirkstoffdesign, Wirkstoffdesign, Arzneimitteldesign, Enzyminhibitor, Tethering, Kristallographie, Structure based drug-design
Referenziert von:

Summary:
Im Rahmen dieser Dissertation wurde eine Auswahl recht verschiedene Ansätze zur Fragment-basierten Leitstruktursuche (fragement-based lead discovery) mit dem Zielprotein Carboanhydrase II durchgeführt. Die verschiedenen Projekte wurden entscheidend durch die Protein Kristallographie unterstützt und methodisch gelenkt. Durch Verbesserung von Strahlungsquellen und der Rechenleistung von Computern hat sich die Protein-Kristallographie in den letzten Jahren zu einem Analytik Instrument entwickelt, welches routinemäßig zur Strukturaufklärung eingesetzt werden kann. Circa 200 bis 250 Datensätze wurden im Rahmen dieser Arbeit gesammelt um Fragestellungen der verschiedenen ambitionierten Projekte mit Focus auf die Strukturbiologie zu beantworten. Wie kann die Wechselwirkung zwischen Proteinen und kleinen Substanzen für Wirkstoffentwicklungen ausgenutzt werden? Ist es möglich, z.B. Reaktionen die in situ ablaufen, durch Protein-Kristallographie zu verfolgen? Kann die Erfolgsquote von Fragment-basierter Kristallographie durch einen Tethering-Ansatz, welcher schwach bindende Fragmente am Protein fixiert, erhöht werden? Die Verfügbarkeit großer Mengen an CA II ist die Grundvoraussetzung um solch eine Bandbreite sehr verschiedener Projekte durchführen zu können. Daher wurde das CA II Gen in das GST gene fusion System kloniert, ein System welches Gen Expression auf sehr hohem Niveau ermöglicht. Das Expressionssystem wurde hinsichtlich der Proteinausbeute optimiert und stellt 30 mg Protein aus 1 L Zellkultur bereit. Etliche CA II Mutanten wurden durch ortsgerichtete Mutation hergestellt und eine Quecksilber-freie Protein-Kristallisation für den Wildtyp und die Mutanten erstellt. Die Durchführung einer prominenten Click-Chemie-Reaktion, der Huisgen Reaktion – eine Cu+ katalysierte 2+3 dipolare Cycloaddition – in der Bindetasche der CA II war das anfängliche Ziel des ersten Projektes dieser Dissertation. Dafür sollte ein künstliches Kupfer-Zentrum an der Oberfläche der CA II eingeführt, und dieses neue katalytische Zentrum für die Bildung von Triazolen aus Alkinen und Aziden ausgenutzt werden. Leider verblieben diese Versuche eines rationalen Designs erfolglos. Dies zeigt auf, dass unser derzeitig noch begrenztes Verständnis über den Zusammenhang zwischen Aminosäure-Mutationen und Proteinarchitektur in komplexen biologischen Systemen, wie z.B. in hoch entwickelten Proteinen, unvorhersehbaren Auswirkungen mit sich bringen kann. Schließlich, eher durch einen glücklichen Zufall als gezieltes Design, konnte die Bildung eines Kupfer-Zentrums an der Oberfläche der CA II zustande gebracht werden. Neben dem zuvor beschriebenen Design eines Metall-Zentrums, wurde das Click-Chemie-Projekt ebenso durch einen neuartigen Tethering-unterstützten Ansatz vorangetrieben. In diesem Ansatz wird eine Reaktionskomponente kovalent an die Proteinoberfläche gebunden, während die zweite Komponente durch einen Sulfonamid-Anker an das Zink-Ion im aktiven Zentrum bindet. Die Reaktion konnte entweder durch Cu+ Ionen oder aber durch die Proteinumgebung ausgelöst werden. Bemerkenswerterweise erfolgte die Protein-induzierte Triazolbildung mit ausgeprägter Regio- sowie Stereoselektivität. Aus dem racemischen Alkingemisch wurde selektiv das 1,5-S-Triazol gebildet. Die Tethering Methode wurde abgesehen von diesem Click-Chemie-Ansatz ebenso für ein Fragment-Screening in Hinblick auf die CA II angewandt. Der Tethering-Ansatz ermöglicht die Identifizierung von Fragmenten mit eher schwacher Affinität zum Zielprotein. Durch einen computerbasierten Docking-Ansatz wurde eine virtuelle Bibliothek von Fragmenten getestet um so eine überschaubare Anzahl an Substanzen für die Synthese auszuwählen. Durch HPLC-MS Messungen konnten viele Fragmente mit einer vielversprechenden Affinität zu CA II identifiziert werden. Einige dieser Substanzen wurden im kovalenten Komplex mit CA II kristallographisch untersucht und zeigten, dass eine Saccharin-Bindetasche an der Protein-Oberfläche mit diesem Tethering-Ansatz erfolgreich untersucht werden kann. Zusätzlich konnte eine zweite Bindetasche an der Oberfläche, bekannt für die Bindung von CA II Aktivatoren, untersucht werden. In einem weiteren Ansatz zur Fragment-basierten Leitstruktursuche wurden vier neue Zink-koordinierende Kopfgruppen an CA Isoenzymen getestet. Eine Komplexstruktur von CA II mit 1,2-HOPTO zeigte einen neuartigen Zn2+ koordinierenden Bindungsmodus mit Wechselwirkungen zu Thr199 und Thr200. Das Fragment, welches zusätzlich perfekt durch ein Wassernetzwerk koordiniert ist, verspricht eine neue Klasse von CA Inhibitoren. Durch die Addition von Substituenten, die mit den hydrophilen und lipophilen Bereichen der CA II Bindetasche wechselwirken, kann die Bindungsaffinität verbessert werden.

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