Dataset Information

Fluoro-Aryl Substituted ?,?^2,3-Peptides in the Development of Foldameric Antiparallel ?-Sheets: A Conformational Study.

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

SUBMITTER: Bucci R

PROVIDER: S-EPMC6454073 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Bucci Raffaella R Contini Alessandro A Clerici Francesca F Beccalli Egle Maria EM Formaggio Fernando F Maffucci Irene I Pellegrino Sara S Gelmi Maria Luisa ML

Frontiers in chemistry 20190402

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 wa ...[more]

PMID: 31001518

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Project description:The development of peptide beta-hairpins is problematic, because folding depends on the amino acid sequence and changes to the sequence can significantly decrease folding. Robust beta-hairpins that can tolerate such changes are attractive tools for studying interactions involving protein beta-sheets and developing inhibitors of these interactions. This paper introduces a new class of peptide models of protein beta-sheets that addresses the problem of separating folding from the sequence. These model beta-sheets are macrocyclic peptides that fold in water to present a pentapeptide beta-strand along one edge; the other edge contains the tripeptide beta-strand mimic Hao [JACS 2000, 122, 7654] and two additional amino acids. The pentapeptide and Hao-containing peptide strands are connected by two delta-linked ornithine (deltaOrn) turns [JACS 2003, 125, 876]. Each deltaOrn turn contains a free alpha-amino group that permits the linking of individual modules to form divalent beta-sheets. These "cyclic modular beta-sheets" are synthesized by standard solid-phase peptide synthesis of a linear precursor followed by solution-phase cyclization. Eight cyclic modular beta-sheets 1a-1h containing sequences based on beta-amyloid and macrophage inflammatory protein 2 were synthesized and characterized by 1H NMR. Linked cyclic modular beta-sheet 2, which contains two modules of 1b, was also synthesized and characterized. 1H NMR studies show downfield alpha-proton chemical shifts, deltaOrn delta-proton magnetic anisotropy, and NOE cross-peaks that establish all compounds but 1c and 1g to be moderately or well folded into a conformation that resembles a beta-sheet. Pulsed-field gradient NMR diffusion experiments show little or no self-association at low (</=2 mM) concentrations. Changes to the residues in the Hao-containing strands of 1c and 1g improve folding and show that folding of the structures can be enhanced without altering the sequence of the pentapeptide strand. Well-folded cyclic modular beta-sheets 1a, 1b, and 1f each have a phenylalanine directly across from Hao, suggesting that cyclic modular beta-sheets containing aromatic residues across from Hao are better folded.

Dataset Information

Fluoro-Aryl Substituted ?,?^2,3-Peptides in the Development of Foldameric Antiparallel ?-Sheets: A Conformational Study.

Publications

Fluoro-Aryl Substituted α,β<sup>2,3</sup>-Peptides in the Development of Foldameric Antiparallel β-Sheets: A Conformational Study.

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Dataset Information

Fluoro-Aryl Substituted ?,?2,3-Peptides in the Development of Foldameric Antiparallel ?-Sheets: A Conformational Study.

Publications

Fluoro-Aryl Substituted α,β<sup>2,3</sup>-Peptides in the Development of Foldameric Antiparallel β-Sheets: A Conformational Study.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Fluoro-Aryl Substituted ?,?^2,3-Peptides in the Development of Foldameric Antiparallel ?-Sheets: A Conformational Study.