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. 2019 Apr 2:7:192.
doi: 10.3389/fchem.2019.00192. eCollection 2019.

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   4 , Sara Pellegrino  1 , Maria Luisa Gelmi  1
Affiliations

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

Raffaella Bucci et al. Front Chem. .

Abstract

α,β2,3-Disteroisomeric foldamers of general formula Boc(S-Ala-β-2R,3R-Fpg)nOMe or Boc(S-Ala-β-2S,3S-Fpg)nOMe 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 β2,3-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 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 β2,3-fluoro amino acid very appealing for the development of bioactive proteolytically stable foldameric β-sheets as modulators of protein-protein interaction (PPI).

Keywords: antiparallel β-sheet; conformational analyses; extended peptide; foldamers; α, β2,3-peptide; β2,3-diaryl-amino acid.

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Figures

Figure 1
Figure 1
Di-, tetra-, and hexa-peptides from S-Ala and β-Fpg.
Scheme 1
Scheme 1
a) i) 1 M HCl, 80°C, 12 h; ii) (Boc2O, DCM, TEA, 25°C, 12 h; b) TFA, CH2Cl2, 0°C, 1 h; c) EDC (1.1 equiv.)/EtCN-oxime(1.1 equiv.), CH2Cl2, 25°C, 3 h.
Figure 2
Figure 2
Amide A portion of the FTIR spectra acquired for 11 (A) and 12 (B) in CDCl3 solution at 0.1 and 1 mM peptide concentrations (cell path lengths of 10 and 1 mm were used, respectively).
Figure 3
Figure 3
Δδ/ΔT NH values for peptides 7 and 8 (273–328 K).
Figure 4
Figure 4
Δδ/ΔT NH values for peptides 12 (273–328 K).
Figure 5
Figure 5
(A) NOEs of peptide 8. (B) Zoom of aromatic region spectrum (CDCl3, 10 mM, 293 K, 400 MHz, 300 ms).
Figure 6
Figure 6
(A) Intra- (continuous arrow) and inter- (dotted arrow) strand NOEs for peptide 11. (B) ROESY zoom of Boc region. (C) ROESY zoom of Me region spectrum (CDCl3, 10 mM, 293 K, 400 MHz, 200 ms).
Figure 7
Figure 7
Top 2 clusters representative structures of m7 (A,B) and m8 (C,D) tetrapeptides. The populations of each cluster are indicated as a percentage. Hydrogen bonds are indicated as dashed black lines.
Figure 8
Figure 8
Representative structures of the two most populated clusters of m11 (A,B) and m12 (C,D) hexapeptides. The population of each cluster is indicated as a percentage. Hydrogen bonds are depicted as dashed black lines.
Figure 9
Figure 9
Comparison of the normalized sampling frequencies of RoG calculated from the last 200 ns of the aMD trajectories of m7, m8, m11, and m12.
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