Comparative α-helicity of cyclic pentapeptides in water

Aline D. De Araujo, Huy N. Hoang, W. Mei Kok, Frederik Diness, Praveer Gupta, Timothy A. Hill, Russell W. Driver, David A. Price, Spiros Liras, David P. Fairlie

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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.

OriginalsprogEngelsk
TidsskriftAngewandte Chemie - International Edition
Vol/bind53
Udgave nummer27
Sider (fra-til)6965-6969
Antal sider5
ISSN1433-7851
DOI
StatusUdgivet - 1 jul. 2014
Udgivet eksterntJa

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