title: The cyclic cystine ladder in θ-defensins is important for structure and stability, but not antibacterial activity.
abstract: θ-Defensins are ribosomally synthesized cyclic peptides found in the leukocytes of some primate species and have promising applications as antimicrobial agents and scaffolds for peptide drugs. The cyclic cystine ladder motif, comprising a cyclic peptide backbone and three parallel disulfide bonds, is characteristic of θ-defensins. In this study, we explore the role of the cyclic peptide backbone and cystine ladder in the structure, stability, and activity of θ-defensins. θ-Defensin analogues with different numbers and combinations of disulfide bonds were synthesized and characterized in terms of their NMR solution structures, serum and thermal stabilities, and their antibacterial and membrane-binding activities. Whereas the structures and stabilities of the peptides were primarily dependent on the number and position of the disulfide bonds, their antibacterial and membrane-binding properties were dependent on the cyclic backbone. The results provide insights into the mechanism of action of θ-defensins and illustrate the potential of θ-defensin analogues as scaffolds for peptide drug design.
authors: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, the University of Queensland, Brisbane, Queensland 4072, Australia.
authors: Anne C
authors: AC
authors: Conibear
authors: K Johan
authors: KJ
authors: Rosengren
authors: Norelle L
authors: NL
authors: Daly
authors: Sónia Troeira
authors: ST
authors: Henriques
authors: David J
authors: DJ
authors: Craik
mesh_terms: D020816:Amino Acid Motifs; D003553:Cystine / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D019906:Nuclear Magnetic Resonance, Biomolecular; D055550:Protein Stability; D017433:Protein Structure, Secondary; D023084:alpha-Defensins / Q000737:chemistry* / Q000235:genetics
chemical_list: D023084:alpha-Defensins; D003553:Cystine