Thioviridamid mit seinen unnatürlichen Aminosäuren als Anregung für die Synthese funktioneller Peptide
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Philipps-Universität Marburg
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Abstract
The present work deals with the strategic and tactical design and synthesis of a peptide natural product using thioviridamide as an example. Thioviridamide as a ribosamally synthesized and post-translationally modified peptide natural product from the class of thioamitides and has numerous modifications. These include five consecutive thioamides (Ala, Met, Val), a dimethylated β-hydroxy-histidine (hdmHis) and an aminovinylcysteine (AviCys), which represents the 19-membered macrocycle linked to the linear thioamide chain. The modular design allowed the modified amino acids to be synthesized via organic synthesis and introduced into the sequence via solid-phase peptide synthesis. In addition to the synthesis, the thioviridamide sequence was initially synthesized with the coding amino acids and, starting from this, systematically varied towards the natural product. Based on these derivatives, an α helical structure was postulated for all lysine (instead of AviCys) mutants, which are in agreement with the analogous natural product thioholgamide A. This was characterized by a low coupling constant of Ala9NH (3J), as well as NOE contacts of H11 to I8. Thioether-containing (cae, lan) macrocycles destabilized the helical structure, whereas histidinium promoted helicity due to its positive charge. The double methylation of His served as inspiration for the synthesis of additional hisitidinium amino acids. These covered aliphatic or benzylic residues and featured 6 or 10-π aromatic or fluor substituents, respectively. These positively charged and hydrophobic aromatic amino acids were incorporated into biologically active peptides, such as rheumatoid arthritis β-hairpin peptide, short ghrelin peptide or short antimicrobial peptides (SAMP). The dimethylnaphthyl-containing histidinium amino acid as SAMP peptide showed a ten fold higher activity against B.subtilis than the reference compound and showed interesting modes of action in membrane assays, which will be verified in further biological assays and provide a starting point for further peptides.
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Created: 2023Issued: 2025-11-26Updated: 2025-05-05
Faculty
Fachbereich Chemie
Language
ger
Data types
DoctoralThesis
DFG-subjects
ThioamideAminovinylcysteinPeptideNMR-Spektrounnatürliche AminosäurenFestphasenpeptidsytheseOrganische SyntheseHistidinThioviridamid
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540
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Klee, Dennis Michael: Thioviridamid mit seinen unnatürlichen Aminosäuren als Anregung für die Synthese funktioneller Peptide. : Philipps-Universität Marburg 2025-11-26. DOI: https://doi.org/10.17192/z2023.0658.