Abstract
The principles of β-sheet folding and design for α-peptidic sequences are well established, while those for sheet mimetics containing homologated amino acid building blocks are still under investigation. To reveal the structure-function relations of β-amino-acid-containing foldamers, we followed a top-down approach to study a series of α/β-peptidic analogs of anginex, a β-sheet-forming antiangiogenic peptide. Eight anginex analogs were developed by systematic α → β(3) substitutions and analyzed by using NMR and CD spectroscopy. The foldamers retained the β-sheet tendency, though with a decreased folding propensity. β-Sheet formation could be induced by a micellar environment, similarly to that of the parent peptide. The destructuring effect was higher when the α → β(3) exchange was located in the β-sheet core. Analysis of the β-sheet stability versus substitution pattern and the local conformational bias of the bulky β(3)V and β(3)I residues revealed that a mismatch between the H-bonding preferences of the α- and β-residues played a minor role in the structure-breaking effect. Temperature-dependent CD and NMR measurements showed that the hydrophobic stabilization was scaled-down for the α/β-peptides. Analysis of the biological activity of the foldamer peptides showed that four anginex derivatives dose-dependently inhibited the proliferation of a mouse endothelial cell line. The α → β(3) substitution strategy applied in this work can be a useful approach to the construction of bioactive β-sheet mimetics with a reduced aggregation tendency and improved pharmacokinetic properties.
Highlights
The design of water-soluble β-sheet models mimicking structural and functional features of proteins is an enduring challenge
Foldameric sequences with unnatural building blocks in the chain are an important class of β-sheet mimetics
The majority of residues in the sheet-forming region of anginex are crucial for bioactivity in in vitro tests.[47,48]. These involve the side-chains responsible for the hydrophobic stabilization of the structure and interaction anchor points over the surface of anginex
Summary
The design of water-soluble β-sheet models mimicking structural and functional features of proteins is an enduring challenge. The N-terminal part (V7−F12), exhibited SSP values corresponding to a random coil structure This was in line with the earlier structural data for anginex, showing that the first strand of the β-sheet was more flexible than the other two.[45] Similar folding patterns were observed for the α/β-analogs, but the overall sheet-forming tendencies of the second and third strands were lower than found for the parent anginex. 14.4 observed for the foldameric analogs, which has a radius increasing effect for a single chain without oligomerization.[56] The analogs (1−8) exhibited apparent hydrodynamic radii in the range 14.0−14.9 Å indicating a small decrease relative to anginex. Proliferation was measured by using XTT test, and the values are given as percentages of the cell proliferation in the absence of peptides
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