Comparative α-Helicity of Cyclic Pentapeptides in Water

• Published in: Angewandte Chemie Vol. 126; no. 27; pp. 7085 - 7089
• Main Authors: de Araujo, Aline D., Hoang, Huy N., Kok, W. Mei, Diness, Frederik, Gupta, Praveer, Hill, Timothy A., Driver, Russell W., Price, David A., Liras, Spiros, Fairlie, David P.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01-07-2014; WILEY‐VCH Verlag
• Subjects: Circulardichroismus; Cyclische Peptide; Helixbildung; Konformationen; α-Helices
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.201310245

Helix‐constrained polypeptides have attracted great interest for modulating protein–protein interactions (PPI). It is not known which are the most effective helix‐inducing strategies for designing PPI agonists/antagonists. Cyclization linkers (X1–X5) were compared here, using circular dichroism and 2D NMR spectroscopy, for α‐helix induction in simple model pentapeptides, Ac‐cyclo(1,5)‐[X1‐Ala‐Ala‐Ala‐X5]‐NH2, in water. In this very stringent test of helix induction, a Lys1→Asp5 lactam linker conferred greatest α‐helicity, hydrocarbon and triazole linkers induced a mix of α‐ and 310‐helicity, while thio‐ and dithioether linkers produced less helicity. The lactam‐linked cyclic pentapeptide was also the most effective α‐helix nucleator attached to a 13‐residue model peptide.
Kovalente Linker zwischen Aminosäure‐Seitenketten in Peptidsequenzen können biologisch aktive α‐helikale Konformationen induzieren, um auf diese Weise Protein‐Protein‐Wechselwirkungen zu modulieren. Ein bestimmter Lactam‐Linker induziert an einem cyclischen Pentapeptid in Wasser eine stärkere α‐Helizität als andere Linker. Außerdem ist er, an längere Peptide geknüpft, ein besserer Helix‐Nukleator.