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

Abstract

α,β 2,3 -Disteroisomeric foldamers of general formula Boc( S- Ala-β-2 R ,3 R- Fpg) n OMe or Boc( S- Ala-β-2 S ,3 S- 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,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-2 R,3R -Fpg, a stable extended β-strand conformation was obtained. Furthermore, β-2 R,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).

Peptide-Based Electrospun Fibers: Current Status and Emerging Developments

“…The main drawback is their lack of proteolytic stability. This issue can be overcome by using peptidomimetics, compounds containing non-natural amino acids or non-peptidic structural elements, capable of mimicking the actions of a natural parent peptide [ 42 , 43 ].…”

“…Indeed, they could be characterized by different secondary structures depending on their amino acid sequences [ 41 ]. The secondary structures determine the 3D folded structures, formed by non-covalent interactions that are at the base of the aggregate formation [ 43 , 44 , 45 ]. In conclusion, very often, peptides with a stable conformation are able to self-assemble, and this is also one of the most important factors for the formation of well-defined electrospun fibers [ 41 ].…”

Fishing in the Toolbox of Cyclic Turn Mimics: a Literature Overview of the Last Decade

“…Bucci et al synthesized a Δ 2 -isoxazoline scaffold, fused with a pyrrolidine ring, of general formula 101, able to stabilize a parallel β-hairpin. [65] Compound 101 was synthesized using a diasteroselective [1,3]-cycloaddition reaction between chloroxime 99 and pyrroline derivative 100 (A) in Scheme 22), whose stereochemical outcome is strictly dependent on the base. Computational studies confirmed that π-interactions between the phenyl substituents of the two reagents favor the formation of the 3aR,6aS-isomer 101 b.…”

“…Benzodiazepinones 120 were synthesized from compounds 124 through Boc protecting group removal, followed by imine formation. Pyrrolo [1,2-d] [1,4] benzodiazepinones 121 and 122 were obtained from olefins 124 as starting materials. Their transformation into the corresponding di-carbonyl compounds through oxidation of double bond was first performed, followed by intramolecular reaction of deprotected amino group with the two carbonyl moieties giving pyrrole ring.…”

“…Peptides are versatile tools for scientists: their huge diversity in structure and in biological functions is indeed an endless inspiration source for a wide range of applications, from pharmaceutical chemistry to material science, [1,2] from catalysis to biomedicine. [3] In this context, peptide mimics are a longstanding goal.…”