Comparative α-helicity of cyclic pentapeptides in water

Abstract

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-X 5]-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 3 10-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. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.