Fluoro-Aryl Substituted α,ß2,3-Peptides in the Development of Foldameric Antiparallel ß-Sheets: A Conformational Study.

α,ß2,3-Disteroisomeric foldamers of general formula Boc(S-Ala-ß-2R,3R-Fpg)nOMe or Boc(S-Ala-ß-2S,3S-Fpg)nOMe were prepared from both enantiomers of syn H-2-(2-F-Phe)-h-PheGly-OH (named ß-Fpg) and S-alanine. Our peptides show two appealing features for biomedical applications: the presence of fluorine, attractive for non-covalent interactions, and aryl groups, crucial for π-stacking. A conformational study was performed, using IR, NMR and computational studies of diastereoisomeric tetra- and hexapeptides containing the ß2,3-amino acid in the R,R- and S,S-stereochemistry, respectively. We found that the stability of peptide conformation is dependent on the stereochemistry of the ß-amino acid. Combining S-Ala with ß-2R,3R-Fpg, a stable extended ß-strand conformation was obtained. Furthermore, ß-2R,3R-Fpg containing hexapeptide self-assembles to form antiparallel ß-sheet structure stabilized by intermolecular H-bonds and π,π-interactions. These features make peptides containing the ß2,3-fluoro amino acid very appealing for the development of bioactive proteolytically stable foldameric ß-sheets as modulators of protein-protein interaction (PPI).