Foldameric alpha/beta-Peptide Analogs of the beta-Sheet-Forming Antiangiogenic Anginex: Structure and Bioactivity

Hegedus, Z [Hegedüs, Zsófia (gyógyszerkémia), szerző] MTA-SZTE Lendület Peptidfoldamer Kutatócsoport (SZTE / GYTK / GYKI); Weber, E* [Wéber, Edit (gyógyszerkémia), szerző] MTA-SZTE Lendület Peptidfoldamer Kutatócsoport (SZTE / GYTK / GYKI); Kriston-Pal, E [Kriston-Pál, Éva (tumorbiológia), szerző] Genetikai Intézet (MTA SZBK); Makra, Ildikó [Makra, Ildikó (biológia), szerző]; Czibula, A [Czibula, Ágnes (Molekuláris genetika), szerző] Genetikai Intézet (MTA SZBK); Monostori, E [Monostori, Éva (Immunológia), szerző] Genetikai Intézet (MTA SZBK); Martinek, TA ✉ [Martinek, Tamás (Gyógyszerkémia), szerző] MTA-SZTE Lendület Peptidfoldamer Kutatócsoport (SZTE / GYTK / GYKI)

Angol nyelvű Tudományos Szakcikk (Folyóiratcikk)
Megjelent: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 0002-7863 1520-5126 135 (44) pp. 16578-16584 2013
  • SJR Scopus - Biochemistry: D1
    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.
    Hivatkozás stílusok: IEEEACMAPAChicagoHarvardCSLMásolásNyomtatás
    2020-07-06 14:48