The principles of beta-sheet folding and design for alpha-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
beta-amino-acid-containing foldamers, we followed a top-down approach to study a series
of alpha/beta-peptidic analogs of anginex, a beta-sheet-forming antiangiogenic peptide.
Eight anginex analogs were developed by systematic alpha --> beta(3) substitutions
and analyzed by using NMR and CD spectroscopy. The foldamers retained the beta-sheet
tendency, though with a decreased folding propensity. beta-Sheet formation could be
induced by a micellar environment, similarly to that of the parent peptide. The destructuring
effect was higher when the alpha --> beta(3) exchange was located in the beta-sheet
core. Analysis of the beta-sheet stability versus substitution pattern and the local
conformational bias of the bulky beta(3)V and beta(3)I residues revealed that a mismatch
between the H-bonding preferences of the alpha- and beta-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 alpha/beta-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
alpha --> beta(3) substitution strategy applied in this work can be a useful approach
to the construction of bioactive beta-sheet mimetics with a reduced aggregation tendency
and improved pharmacokinetic properties.
