Heimer, Pascal: Influence of the Conformation of Conotoxins on their Bioactivity. - Bonn, 2017. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5n-49258
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5n-49258,
author = {{Pascal Heimer}},
title = {Influence of the Conformation of Conotoxins on their Bioactivity},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2017,
month = dec,

note = {In the last decade peptides filled the gap between small molecule drugs and biologics as therapeutics. A rich source of such peptides represents the venom of different animals evolved over millions of years. Conotoxins are small, disulfide-rich neuropeptides isolated from cone snails of the genus Conus, which act on different biological targets like ion channels or receptors. These toxins contain a complex cocktail of bioactive substances and are utilized for self-defence or hunting prey. With over 700 species known, these marine invertebrates reveal a large potential of novel pharmacologically active molecules, e.g. for the treatment of severe and chronic pain. Although peptide synthesis is established nowadays, preparation and characterization of disulfide-rich peptides is still a challenge. The formation of different disulfide isomers is one main issue facilitating the elucidation of such disulfide-rich peptides and proteins.
The aim of this work was to investigate the folding of small multiple disulfide-bridged peptides under different conditions and perform structure-activity relationship studies of the resulting products. Within the scope of this project different conotoxins were synthesized by solidphase peptide synthesis. Disulfide formation was achieved by different methods i.e. oxidative self-folding, oxidation in Ionic Liquids and successive oxidation in combination with an orthogonal protecting group strategy. The oxidized conotoxins were systematically investigated and characterized with different analytical methods. Elucidation of the final three-dimensional structure was performed by NMR spectroscopy. Furthermore, determination of the disulfide connectivity was investigated by different methods of mass spectrometric analysis (LC-ESI and MALDI) after partial reduction and derivatization. The results of all applied analytical methods revealed their advantages and limitations for the discrimination of different disulfide isomers within conotoxins depending on primary amino acid sequence. Biological testing of the synthesized peptides on ion channels was performed in parallel with computational studies to enlighten the structure-activity relationships. The work presented in this thesis significantly extends the knowledge about conotoxins and disulfide formation, their impact with respect to biological activity, and the challenging characterization and structure elucidation procedures.},

url = {https://hdl.handle.net/20.500.11811/7315}

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