The cyclic cystine ladder of theta-defensins as a stable, bifunctional scaffold: a proof-of-concept study using the integrin-binding RGD motif

Conibear, Anne C., Bochen, Alexander, Rosengren, K. Johan, Stupar, Petar, Wang, Conan, Kessler, Horst and Craik, David J. (2014) The cyclic cystine ladder of theta-defensins as a stable, bifunctional scaffold: a proof-of-concept study using the integrin-binding RGD motif. ChemBioChem, 15 3: 451-459. doi:10.1002/cbic.201300568

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Author Conibear, Anne C.
Bochen, Alexander
Rosengren, K. Johan
Stupar, Petar
Wang, Conan
Kessler, Horst
Craik, David J.
Title The cyclic cystine ladder of theta-defensins as a stable, bifunctional scaffold: a proof-of-concept study using the integrin-binding RGD motif
Journal name ChemBioChem   Check publisher's open access policy
ISSN 1439-4227
1439-7633
Publication date 2014-02-01
Year available 2014
Sub-type Article (original research)
DOI 10.1002/cbic.201300568
Open Access Status Not yet assessed
Volume 15
Issue 3
Start page 451
End page 459
Total pages 9
Place of publication Weinheim, Germany
Publisher Wiley - V C H Verlag
Language eng
Abstract Peptides have the specificity and size required to target the protein-protein interactions involved in many diseases. Some cyclic peptides have been utilised as scaffolds for peptide drugs because of their stability; however, other cyclic peptide scaffolds remain to be explored. theta-Defensins are cyclic peptides from mammals; they are characterised by a cyclic cystine ladder motif and have low haemolytic and cytotoxic activity. Here we demonstrate the potential of the cyclic cystine ladder as a scaffold for peptide drug design by introducing the integrin-binding Arg-Gly-Asp (RGD) motif into the theta-defensin RTD-1. The most active analogue had an IC50 of 18 nm for the alpha(v)beta(3) integrin as well as high serum stability, thus demonstrating that a desired bioactivity can be imparted to the cyclic cystine ladder. This study highlights how theta-defensins can provide a stable and conformationally restrained scaffold for bioactive epitopes in a beta-strand or turn conformation. Furthermore, the symmetry of the cyclic cystine ladder presents the opportunity to design peptides with dual bioactive epitopes to increase activity and specificity.
Formatted abstract
Peptides have the specificity and size required to target the protein–protein interactions involved in many diseases. Some cyclic peptides have been utilised as scaffolds for peptide drugs because of their stability; however, other cyclic peptide scaffolds remain to be explored. θ-Defensins are cyclic peptides from mammals; they are characterised by a cyclic cystine ladder motif and have low haemolytic and cytotoxic activity. Here we demonstrate the potential of the cyclic cystine ladder as a scaffold for peptide drug design by introducing the integrin-binding Arg-Gly-Asp (RGD) motif into the θ-defensin RTD-1. The most active analogue had an IC50 of 18 nᴍ for the αvβ3 integrin as well as high serum stability, thus demonstrating that a desired bioactivity can be imparted to the cyclic cystine ladder. This study highlights how θ-defensins can provide a stable and conformationally restrained scaffold for bioactive epitopes in a β-strand or turn conformation. Furthermore, the symmetry of the cyclic cystine ladder presents the opportunity to design peptides with dual bioactive epitopes to increase activity and specificity.
Keyword Cyclic cystine ladder
Drug design
Integrin-binding
Peptides
theta-Defensins
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID DP0984390
APP1026501
APP631420
Institutional Status UQ
Additional Notes Article first published online: 2 January 2014.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Biomedical Sciences Publications
Institute for Molecular Bioscience - Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 17 times in Thomson Reuters Web of Science Article | Citations
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Created: Tue, 14 Jan 2014, 00:15:19 EST by Susan Allen on behalf of Chemistry, Department of