Exploiting aromatic interactions for β-peptide foldamer helix stabilization: A significant design element

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Abstract

Tetrameric H10/12 helix stabilization was achieved by the application of aromatic side-chains in β-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 β-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. A stabilizing chain: The incorporation of ATENAC building blocks into alternating heterochiral cyclic cis-β-amino acid sequences led to the stabilization of a β-peptidic alternating H10/12 helix. Vesicle formation was observed for the oligomers in methanol solution, thus confirming the formation of a helical secondary structure. This is the first report of the self-association of tetrameric helical oligomers in the form of vesicles (see figure).

Original languageEnglish
Pages (from-to)4591-4597
Number of pages7
JournalChemistry - A European Journal
Volume20
Issue number16
DOIs
Publication statusPublished - Apr 14 2014

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Keywords

  • foldamers
  • helix stabilization
  • pi interactions
  • self-assembly
  • β-peptides

ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry

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