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Targeting the Final Step of Blood Coagulation
Structure-Activity-Relationship Studies on the Factor XIIIa Inhibitor Tridegin

dc.contributor.advisorImhof, Diana
dc.contributor.authorBöhm, Miriam
dc.date.accessioned2020-04-21T09:24:45Z
dc.date.available2020-04-21T09:24:45Z
dc.date.issued23.09.2015
dc.identifier.urihttps://hdl.handle.net/20.500.11811/6536
dc.description.abstractThe prophylaxis and therapy of thrombotic diseases is one of the major columns supporting our continuously increasing life expectancy and health. The transglutaminase factor XIIIa (FXIIIa), which is part of the blood coagulation cascade, therefore is an interesting target for antithrombotic and thrombolytic treatment with enzyme inhibitors. Additionally, powerful and specific FXIIIa inhibitors are valuable research tools to elucidate the multiple functions of FXIIIa in more detail. An example for such a powerful inhibitor of FXIIIa can be found in nature: Tridegin, a 66mer peptide was first isolated from the salivary gland of the giant amazon leech Haementeria ghilianii in 1997 and is still one of the most potent and specific FXIIIa inhibitors described. The aim of this thesis is to gain access to the peptide by different preparation methods and to characterize in detail the inhibitory mechanism and structure of this interesting peptide. In the course of this research tridegin was synthesized by solid-phase peptide synthesis followed by oxidative self folding to form disulfide bonds. Additionally, recombinant expression of the peptide in Escherichia coli was performed. Functional analysis by enzyme activity and binding assays revealed that the major inhibitory action is localized in the C-terminal part of the peptide, whereas the N-terminal part contributes to binding affinity. The disulfide connectivity of both the synthetic and the recombinant peptide variant was elucidated by mass spectrometric analysis and showed that three different disulfide-linked isomers were formed. Subsequently, molecular modeling of all three isomers was performed and the models were docked to the FXIII-A° structure. In general, this work greatly increases the understanding of the natural FXIIIa inhibitor tridegin, which provides the scientific community with a valuable research tool and a potential lead structure for the development of new FXIIIa inhibitors.
dc.language.isoeng
dc.rightsIn Copyright
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/
dc.subjectPeptid
dc.subjectGerinnung
dc.subjectFaktor XIII
dc.subjectHemmstoff
dc.subjectBlutegel
dc.subjectPeptide
dc.subjectCoagulation
dc.subjectFactor XIII
dc.subjectInhibitor
dc.subjectLeech
dc.subject.ddc540 Chemie
dc.subject.ddc615 Pharmakologie, Therapeutik
dc.titleTargeting the Final Step of Blood Coagulation
dc.title.alternativeStructure-Activity-Relationship Studies on the Factor XIIIa Inhibitor Tridegin
dc.typeDissertation oder Habilitation
dc.publisher.nameUniversitäts- und Landesbibliothek Bonn
dc.publisher.locationBonn
dc.rights.accessRightsopenAccess
dc.identifier.urnhttps://nbn-resolving.org/urn:nbn:de:hbz:5n-41288
ulbbn.pubtypeErstveröffentlichung
ulbbnediss.affiliation.nameRheinische Friedrich-Wilhelms-Universität Bonn
ulbbnediss.affiliation.locationBonn
ulbbnediss.thesis.levelDissertation
ulbbnediss.dissID4128
ulbbnediss.date.accepted02.06.2015
ulbbnediss.instituteMathematisch-Naturwissenschaftliche Fakultät : Fachgruppe Pharmazie / Pharmazeutisches Institut
ulbbnediss.fakultaetMathematisch-Naturwissenschaftliche Fakultät
dc.contributor.coRefereeGütschow, Michael


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