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Article

NMR-Based Structural Characterization of a Two-Disulfide-Bonded Analogue of the FXIIIa Inhibitor Tridegin: New Insights into Structure–Activity Relationships

1
Pharmaceutical Biochemistry and Bioanalytics, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany
2
BioSolveIT GmbH, An der Ziegelei 79, D-53757 Sankt Augustin, Germany
3
Institute of Pharmaceutical Chemistry, Philipps University of Marburg, Marbacher Weg 6, 35032 Marburg, Germany
4
Leibniz Institute on Aging—Fritz-Lipmann-Institute, Beutenbergstr. 11, D-07745 Jena, Germany
5
Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Sigmund-Freud-Str. 25, D-53127 Bonn, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(2), 880; https://doi.org/10.3390/ijms22020880
Received: 23 December 2020 / Revised: 10 January 2021 / Accepted: 12 January 2021 / Published: 17 January 2021
(This article belongs to the Special Issue Fibrinogen/Fibrin, Factor XIII and Fibrinolysis in Diseases)
The saliva of blood-sucking leeches contains a plethora of anticoagulant substances. One of these compounds derived from Haementeria ghilianii, the 66mer three-disulfide-bonded peptide tridegin, specifically inhibits the blood coagulation factor FXIIIa. Tridegin represents a potential tool for antithrombotic and thrombolytic therapy. We recently synthesized two-disulfide-bonded tridegin variants, which retained their inhibitory potential. For further lead optimization, however, structure information is required. We thus analyzed the structure of a two-disulfide-bonded tridegin isomer by solution 2D NMR spectroscopy in a combinatory approach with subsequent MD simulations. The isomer was studied using two fragments, i.e., the disulfide-bonded N-terminal (Lys1–Cys37) and the flexible C-terminal part (Arg38–Glu66), which allowed for a simplified, label-free NMR-structure elucidation of the 66mer peptide. The structural information was subsequently used in molecular modeling and docking studies to provide insights into the structure–activity relationships. The present study will prospectively support the development of anticoagulant-therapy-relevant compounds targeting FXIIIa. View Full-Text
Keywords: coagulation factor XIIIa; transglutaminase; coagulation cascade; tridegin; peptide inhibitor; cysteine-rich; disulfide bonds; NMR spectroscopy; structure analysis coagulation factor XIIIa; transglutaminase; coagulation cascade; tridegin; peptide inhibitor; cysteine-rich; disulfide bonds; NMR spectroscopy; structure analysis
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MDPI and ACS Style

Schmitz, T.; Paul George, A.A.; Nubbemeyer, B.; Bäuml, C.A.; Steinmetzer, T.; Ohlenschläger, O.; Biswas, A.; Imhof, D. NMR-Based Structural Characterization of a Two-Disulfide-Bonded Analogue of the FXIIIa Inhibitor Tridegin: New Insights into Structure–Activity Relationships. Int. J. Mol. Sci. 2021, 22, 880. https://doi.org/10.3390/ijms22020880

AMA Style

Schmitz T, Paul George AA, Nubbemeyer B, Bäuml CA, Steinmetzer T, Ohlenschläger O, Biswas A, Imhof D. NMR-Based Structural Characterization of a Two-Disulfide-Bonded Analogue of the FXIIIa Inhibitor Tridegin: New Insights into Structure–Activity Relationships. International Journal of Molecular Sciences. 2021; 22(2):880. https://doi.org/10.3390/ijms22020880

Chicago/Turabian Style

Schmitz, Thomas, Ajay A. Paul George, Britta Nubbemeyer, Charlotte A. Bäuml, Torsten Steinmetzer, Oliver Ohlenschläger, Arijit Biswas, and Diana Imhof. 2021. "NMR-Based Structural Characterization of a Two-Disulfide-Bonded Analogue of the FXIIIa Inhibitor Tridegin: New Insights into Structure–Activity Relationships" International Journal of Molecular Sciences 22, no. 2: 880. https://doi.org/10.3390/ijms22020880

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