AUTHOR=Bucci Raffaella , Contini Alessandro , Clerici Francesca , Beccalli Egle Maria , Formaggio Fernando , Maffucci Irene , Pellegrino Sara , Gelmi Maria Luisa 

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

JOURNAL=Frontiers in Chemistry

VOLUME=7

YEAR=2019

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2019.00192

DOI=10.3389/fchem.2019.00192

ISSN=2296-2646

ABSTRACT=<p>α,β<sup>2,3</sup>-Disteroisomeric foldamers of general formula Boc(<italic>S-</italic>Ala-β-2<italic>R</italic>,3<italic>R-</italic>Fpg)<sub>n</sub>OMe or Boc(<italic>S-</italic>Ala-β-2<italic>S</italic>,3<italic>S-</italic>Fpg)<sub>n</sub>OMe were prepared from both enantiomers of <italic>syn</italic> H-2-(2-F-Phe)-h-PheGly-OH (named β-Fpg) and <italic>S-</italic>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 β<sup>2,3</sup>-amino acid in the <italic>R,R</italic>- and <italic>S,S</italic>-stereochemistry, respectively. We found that the stability of peptide conformation is dependent on the stereochemistry of the β-amino acid. Combining <italic>S</italic>-Ala with β-2<italic>R,3R</italic>-Fpg, a stable extended β-strand conformation was obtained. Furthermore, β-2<italic>R,3R</italic>-Fpg containing hexapeptide self-assembles to form antiparallel β-sheet structure stabilized by intermolecular H-bonds and π,π-interactions. These features make peptides containing the β<sup>2,3</sup>-fluoro amino acid very appealing for the development of bioactive proteolytically stable foldameric β-sheets as modulators of protein-protein interaction (PPI).</p>