Comparative α-helicity of cyclic pentapeptides in water

Aline D. de Araujo; Huy N. Hoang; W. Mei Kok; Frederik Diness; Praveer Gupta; Russell W. Driver; David A. Price; Spiros Liras; David P. Fairlie

doi:10.1002/anie.201310245

Comparative α-helicity of cyclic pentapeptides in water

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

105 Citations (Scopus)

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.

Original language	English
Journal	Angewandte Chemie International Edition
Volume	53
Issue number	27
Pages (from-to)	6965-6969
Number of pages	5
ISSN	1433-7851
DOIs	https://doi.org/10.1002/anie.201310245
Publication status	Published - 1 Jul 2014
Externally published	Yes

Keywords

Amino Acid Sequence
Circular Dichroism
Magnetic Resonance Spectroscopy
Oligopeptides
Peptides, Cyclic
Protein Structure, Secondary
Temperature
Water

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title = "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.",

keywords = "Amino Acid Sequence, Circular Dichroism, Magnetic Resonance Spectroscopy, Oligopeptides, Peptides, Cyclic, Protein Structure, Secondary, Temperature, Water",

author = "{de Araujo}, {Aline D.} and Hoang, {Huy N.} and Kok, {W. Mei} and Frederik Diness and Praveer Gupta and Driver, {Russell W.} and Price, {David A.} and Spiros Liras and Fairlie, {David P.}",

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doi = "10.1002/anie.201310245",

language = "English",

volume = "53",

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TY - JOUR

T1 - Comparative α-helicity of cyclic pentapeptides in water

AU - de Araujo, Aline D.

AU - Hoang, Huy N.

AU - Kok, W. Mei

AU - Diness, Frederik

AU - Gupta, Praveer

AU - Driver, Russell W.

AU - Price, David A.

AU - Liras, Spiros

AU - Fairlie, David P.

PY - 2014/7/1

Y1 - 2014/7/1

N2 - 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.

AB - 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.

KW - Amino Acid Sequence

KW - Circular Dichroism

KW - Magnetic Resonance Spectroscopy

KW - Oligopeptides

KW - Peptides, Cyclic

KW - Protein Structure, Secondary

KW - Temperature

KW - Water

U2 - 10.1002/anie.201310245

DO - 10.1002/anie.201310245

M3 - Journal article

C2 - 24828311

SN - 1433-7851

VL - 53

SP - 6965

EP - 6969

JO - Angewandte Chemie International Edition

JF - Angewandte Chemie International Edition

IS - 27

ER -

Comparative α-helicity of cyclic pentapeptides in water

Abstract

Keywords

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