TY  - JOUR
AU  - Hegedüs, Zsófia
AU  - Wéber, Edit
AU  - Kriston-Pál, Éva
AU  - Makra, Ildikó
AU  - Czibula, Ágnes
AU  - Monostori, Éva
AU  - Martinek, Tamás
TI  - Foldameric α/β-Peptide Analogs of the β-Sheet-Forming Antiangiogenic Anginex: Structure and Bioactivity
JF  - JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
J2  - J AM CHEM SOC
VL  - 135
PY  - 2013
IS  - 44
SP  - 16578
EP  - 16584
PG  - 7
SN  - 0002-7863
DO  - 10.1021/ja408054f
UR  - https://m2.mtmt.hu/api/publication/2459240
ID  - 2459240
AB  - 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.
LA  - English
DB  - MTMT
ER  -