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

Raffaella Bucci (1) , Alessandro Contini (1) , Francesca Clerici (1) , Egle Maria Beccalli (1) , Fernando Formaggio (2) , Irene Maffucci (3) , Sara Pellegrino (1) , Maria Luisa Gelmi (1)

1 UNIMI - Università degli Studi di Milano = University of Milan
2 Dipartimento di Scienze Chimiche [Padova]
3 GEC - Génie Enzymatique et Cellulaire

α,β 2,3-Disteroisomeric foldamers of general formula Boc(S-Ala-β-2R,3R-Fpg) n OMe or Boc(S-Ala-β-2S,3S-Fpg) n OMe were prepared from both enantiomers of syn H-2-(2-F-Phe)-h-PheGly-OH (named β-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 β 2,3-amino acid in the R,Rand S,S-stereochemistry, respectively. We found that the stability of peptide conformation is dependent on the stereochemistry of the β-amino acid. Combining S-Ala with β-2R,3R-Fpg, a stable extended β-strand conformation was obtained. Furthermore, β-2R,3R-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 2,3-fluoro amino acid very appealing for the development of bioactive proteolytically stable foldameric β-sheets as modulators of protein-protein interaction (PPI).

Domaines: Bio-Informatique, Biologie Systémique [q-bio.QM]

Raffaella Bucci, Alessandro Contini, Francesca Clerici, Egle Maria Beccalli, Fernando Formaggio, et al.. Fluoro-Aryl Substituted α,β2,3-Peptides in the Development of Foldameric Antiparallel β-Sheets: A Conformational Study. Frontiers in Chemistry, In press, 7 (11), pp.4637-4648. ⟨10.3389/fchem.2019.00192⟩. ⟨hal-03359408⟩