title: Exploiting aromatic interactions for β-peptide foldamer helix stabilization: a significant design element.
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.
authors.affiliation: Institute of Pharmaceutical Chemistry, University of Szeged, Eötvös u. 6, 6720 Szeged (Hungary), Fax: (+36) 62-545705.
authors.forename: István M
authors.initials: IM
authors.lastname: Mándity
authors.forename: Antonella
authors.initials: A
authors.lastname: Monsignori
authors.forename: Lívia
authors.initials: L
authors.lastname: Fülöp
authors.forename: Enikö
authors.initials: E
authors.lastname: Forró
authors.forename: Ferenc
authors.initials: F
authors.lastname: Fülöp
mesh_terms: D002942:Circular Dichroism; D041961:Deuterium Exchange Measurement; D057927:Hydrophobic and Hydrophilic Interactions; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D017510:Protein Folding; D017433:Protein Structure, Secondary
chemical_list: D010455:Peptides
keywords: foldamers; helix stabilization; pi interactions; self-assembly; β-peptides