Foldameric 伪/尾-Peptide Analogs of the 尾-Sheet-Forming Antiangiogenic Anginex: Structure and Bioactivity

详细信息    查看全文

• 作者：Zs贸fia Heged眉s ; Edit W茅ber ; 脡va Kriston-P谩l ; Ildik贸 Makra ; 脕gnes Czibula ; 脡va Monostori ; Tam谩s A. Martinek
• 刊名：Journal of the American Chemical Society
• 出版年：2013
• 出版时间：November 6, 2013
• 年：2013
• 卷：135
• 期：44
• 页码：16578-16584
• 全文大小：434K
• 年卷期：v.135,no.44(November 6, 2013)
• ISSN：1520-5126

文摘

The principles of 尾-sheet folding and design for 伪-peptidic sequences are well established, while those for sheet mimetics containing homologated amino acid building blocks are still under investigation. To reveal the structure鈥揻unction relations of 尾-amino-acid-containing foldamers, we followed a top-down approach to study a series of 伪/尾-peptidic analogs of anginex, a 尾-sheet-forming antiangiogenic peptide. Eight anginex analogs were developed by systematic 伪 鈫? 尾<sup>3sup> substitutions and analyzed by using NMR and CD spectroscopy. The foldamers retained the 尾-sheet tendency, though with a decreased folding propensity. 尾-Sheet formation could be induced by a micellar environment, similarly to that of the parent peptide. The destructuring effect was higher when the 伪 鈫?尾<sup>3sup> exchange was located in the 尾-sheet core. Analysis of the 尾-sheet stability versus substitution pattern and the local conformational bias of the bulky 尾<sup>3sup>V and 尾<sup>3sup>I residues revealed that a mismatch between the H-bonding preferences of the 伪- and 尾-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 伪/尾-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 伪 鈫?尾<sup>3sup> substitution strategy applied in this work can be a useful approach to the construction of bioactive 尾-sheet mimetics with a reduced aggregation tendency and improved pharmacokinetic properties.