title: The cyclic cystine ladder of theta-defensins as a stable, bifunctional scaffold: A proof-of-concept study using the integrin-binding RGD motif.
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 nM for the αv β3 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.
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Brisbane, St. Lucia, Brisbane, QLD 4072 (Australia).
authors.forename: Anne C
authors.initials: AC
authors.lastname: Conibear
authors.forename: Alexander
authors.initials: A
authors.lastname: Bochen
authors.forename: K Johan
authors.initials: KJ
authors.lastname: Rosengren
authors.forename: Petar
authors.initials: P
authors.lastname: Stupar
authors.forename: Conan
authors.initials: C
authors.lastname: Wang
authors.forename: Horst
authors.initials: H
authors.lastname: Kessler
authors.forename: David J
authors.initials: DJ
authors.lastname: Craik
mesh_terms: D000818:Animals; D003553:Cystine / Q000737:chemistry*; D023082:Defensins / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D039302:Integrin alphaVbeta3 / Q000737:chemistry / Q000378:metabolism*; D009842:Oligopeptides / Q000737:chemistry*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D023082:Defensins; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; C450142:theta-defensin; D003553:Cystine; C047981:arginyl-glycyl-aspartic acid
keywords: cyclic cystine ladder; drug design; integrin-binding; peptides; theta-defensins