Exploiting Aromatic Interactions for [beta]-Peptide Foldamer Helix Stabilization: A Significant Design Element

Tetrameric H10/12 helix stabilization was achieved by the application of aromatic side-chains in [beta]-peptide oligomers by intramolecular backbone-side chain CH-π interactions. Because of the enlarged hydrophobic surface of the oligomers, a further aim was the investigation of the self-assembly in...

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Veröffentlicht in:Chemistry : a European journal 2014-04, Vol.20 (16), p.4591-4597
Hauptverfasser: Mandity, István M, Monsignori, Antonella, Fulop, Lívia, ro, Enikö, Fulop, Ferenc
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Sprache:eng
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Zusammenfassung:Tetrameric H10/12 helix stabilization was achieved by the application of aromatic side-chains in [beta]-peptide oligomers by intramolecular backbone-side chain CH-π interactions. Because of the enlarged hydrophobic surface of the oligomers, a further aim was the investigation of the self-assembly in a polar medium for the [beta]-peptide H10/12 helices. NMR, ECD, and molecular modeling results indicated that the oligomers formed by cis-[1S,2S]- or cis-[1R,2R]-1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (ATENAC) and cis-[1R,2S]- or cis-[1S,2R]-2-aminocyclohex-3-enecarboxylic acid (ACHEC) residues promote stable H10/12 helix formation with an alternating backbone configuration even at the tetrameric chain length. These results support the view that aromatic side-chains can be applied for helical structure stabilization. Importantly, this is the first observation of a stable H10/12 helix with tetrameric chain-length. The hydrophobically driven self-assembly was achieved for the helix-forming oligomers, seen as vesicles in transmission electron microscopy images. The self-association phenomenon, which supports the helical secondary structure of these oligomers, depends on the hydrophobic surface area, because a higher number of aromatic side-chains yielded larger vesicles. These results serve as an essential element for the design of helices relating to the H10/12 helix. Moreover, they open up a novel area for bioactive foldamer construction, while the hydrophobic area gained through the aromatic side-chains may yield important receptor-ligand interaction surfaces, which can provide amplified binding strength. [PUBLICATION ABSTRACT]
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.201304448