Comparative α-Helicity of Cyclic Pentapeptides in Water

• Published in: Angewandte Chemie International Edition Vol. 53; no. 27; pp. 6965 - 6969
• 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: Amino Acid Sequence; Circular Dichroism; cyclic peptides; helix induction; Magnetic Resonance Spectroscopy; NMR structure; Oligopeptides - chemistry; Peptides, Cyclic - chemistry; Protein Structure, Secondary; Temperature; Water - chemistry; α-helix; cyclic peptides; NMR structure; α-helix; circular dichroism; helix induction
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.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.
Covalent linkers between amino acid side chains in peptide sequences can induce bioactive α‐helical conformations that modulate protein–protein interactions. A specific lactam linker is shown here to confer more α‐helicity than other cross‐links to a cyclic pentapeptide in water, and to be a better helix nucleator when attached to longer peptides.