Foldameric α/β-Peptide Analogs of the β‑Sheet-Forming Antiangiogenic Anginex: Structure and Bioactivity

The principles of β-sheet folding and design for α-peptidic sequences are well established, while those for sheet mimetics containing homologated amino acid building blocks are still under investigation. To reveal the structure–function relations of β-amino-acid-containing foldamers, we followed a t...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2013-11, Vol.135 (44), p.16578-16584
Main Authors: Hegedüs, Zsófia, Wéber, Edit, Kriston-Pál, Éva, Makra, Ildikó, Czibula, Ágnes, Monostori, Éva, Martinek, Tamás A
Format: Article
Language:English
Subjects:
Animals
Cell Line
Cell Proliferation - drug effects
Dose-Response Relationship, Drug
Endothelial Cells - drug effects
Mice
Models, Molecular
Peptides - chemical synthesis
Peptides - chemistry
Peptides - pharmacology
Protein Folding
Protein Structure, Secondary
Structure-Activity Relationship
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Summary:The principles of β-sheet folding and design for α-peptidic sequences are well established, while those for sheet mimetics containing homologated amino acid building blocks are still under investigation. To reveal the structure–function relations of β-amino-acid-containing foldamers, we followed a top-down approach to study a series of α/β-peptidic analogs of anginex, a β-sheet-forming antiangiogenic peptide. Eight anginex analogs were developed by systematic α → β3 substitutions and analyzed by using NMR and CD spectroscopy. The foldamers retained the β-sheet tendency, though with a decreased folding propensity. β-Sheet formation could be induced by a micellar environment, similarly to that of the parent peptide. The destructuring effect was higher when the α → β3 exchange was located in the β-sheet core. Analysis of the β-sheet stability versus substitution pattern and the local conformational bias of the bulky β3V and β3I residues revealed that a mismatch between the H-bonding preferences of the α- and β-residues played a minor role in the structure-breaking effect. Temperature-dependent CD and NMR measurements showed that the hydrophobic stabilization was scaled-down for the α/β-peptides. Analysis of the biological activity of the foldamer peptides showed that four anginex derivatives dose-dependently inhibited the proliferation of a mouse endothelial cell line. The α → β3 substitution strategy applied in this work can be a useful approach to the construction of bioactive β-sheet mimetics with a reduced aggregation tendency and improved pharmacokinetic properties.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja408054f