title: Transforming conotoxins into cyclotides: Backbone cyclization of P-superfamily conotoxins.
abstract: Peptide backbone cyclization is a widely used approach to improve the activity and stability of small peptides but until recently it had not been applied to peptides with multiple disulfide bonds. Conotoxins are disulfide-rich conopeptides derived from the venoms of cone snails that have applications in drug design and development. However, because of their peptidic nature, they can suffer from poor bioavailability and poor stability in vivo. In this study two P-superfamily conotoxins, gm9a and bru9a, were backbone cyclized by joining the N- and C-termini with short peptide linkers using intramolecular native chemical ligation chemistry. The cyclized derivatives had conformations similar to the native peptides showing that backbone cyclization can be applied to three disulfide-bonded peptides with cystine knot motifs. Cyclic gm9a was more potent at high voltage-activated (HVA) calcium channels than its acyclic counterpart, highlighting the value of this approach in developing active and stable conotoxins containing cyclic cystine knot motifs.
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia.
authors.forename: Muharrem
authors.initials: M
authors.lastname: Akcan
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Clark
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia.
authors.forename: Norelle L
authors.initials: NL
authors.lastname: Daly
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia.
authors.forename: Anne C
authors.initials: AC
authors.lastname: Conibear
authors.affiliation: Health Innovations Research Institute, RMIT University, Bundoora, VIC, 3083, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: de Faoite
authors.affiliation: Department of Chemistry and Biochemistry, Florida Atlantic University, FL, 33431, USA.
authors.forename: Mari D
authors.initials: MD
authors.lastname: Heghinian
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, QLD, 4072, Australia.
authors.forename: Talwar
authors.initials: T
authors.lastname: Sahil
authors.affiliation: Health Innovations Research Institute, RMIT University, Bundoora, VIC, 3083, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.affiliation: Department of Chemistry and Biochemistry, Florida Atlantic University, FL, 33431, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Marí
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Craik
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020916:Conotoxins / Q000737:chemistry* / Q000494:pharmacology; D003500:Cyclization; D047169:Cyclotides / Q000138:chemical synthesis*; D004331:Drosophila melanogaster; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D008969:Molecular Sequence Data; D066244:Proton Magnetic Resonance Spectroscopy; D051381:Rats; D017208:Rats, Wistar; D017386:Sequence Homology, Amino Acid
chemical_list: D020916:Conotoxins; D047169:Cyclotides
keywords: conotoxins; cyclic peptide; cyclization; cystine knot; drug design