Fluoro-Aryl Substituted α,β2,3-Peptides in the Development of Foldameric Antiparallel β-Sheets: A Conformational Study

alpha,beta(2,3)-Disteroisomeric foldamers of general formula Boc(S-Ala-beta-2R,3R-Fpg)(n) OMe or Boc(S-Ala-beta-2S,3S-Fpg)(n) OMe were prepared from both enantiomers of syn H-2-(2-F-Phe)-h-PheGly-OH (named beta-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 pi-stacking. A conformational study was performed, using IR, NMR and computational studies of diastereoisomeric tetra- and hexapeptides containing the beta(2,3)-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 beta-amino acid. Combining S-Ala with beta-2R,3R-Fpg, a stable extended beta-strand conformation was obtained. Furthermore, beta-2R,3R-Fpg containing hexapeptide self-assembles to formantiparallel beta sheet structure stabilized by intermolecular H-bonds and pi, pi-interactions. These features make peptides containing the beta(2,3)-fluoro amino acid very appealing for the development of bioactive proteolytically stable foldameric beta-sheets as modulators of protein-protein interaction (PPI).