title: Structure-Activity Studies of Cysteine-Rich α-Conotoxins that Inhibit High-Voltage-Activated Calcium Channels via GABA(B) Receptor Activation Reveal a Minimal Functional Motif.
abstract: α-Conotoxins are disulfide-rich peptides that target nicotinic acetylcholine receptors. Recently we identified several α-conotoxins that also modulate voltage-gated calcium channels by acting as G protein-coupled GABA(B) receptor (GABA(B)R) agonists. These α-conotoxins are promising drug leads for the treatment of chronic pain. To elucidate the diversity of α-conotoxins that act through this mechanism, we synthesized and characterized a set of peptides with homology to α-conotoxins known to inhibit high voltage-activated calcium channels via GABA(B)R activation. Remarkably, all disulfide isomers of the active α-conotoxins Pu1.2 and Pn1.2, and the previously studied Vc1.1 showed similar levels of biological activity. Structure determination by NMR spectroscopy helped us identify a simplified biologically active eight residue peptide motif containing a single disulfide bond that is an excellent lead molecule for developing a new generation of analgesic peptide drugs.
authors.affiliation: Institute for Molecular Biosciences, The University of Queensland, Brisbane, Qld, 4072, Australia.
authors.forename: Bodil B
authors.initials: BB
authors.lastname: Carstens
authors.affiliation: Health Innovations Research Institute, RMIT University, Melbourne, Vic, 3083, Australia.
authors.forename: Géza
authors.initials: G
authors.lastname: Berecki
authors.affiliation: School of Biomedical Science, The University of Queensland, Brisbane, Qld, 4072, Australia.
authors.forename: James T
authors.initials: JT
authors.lastname: Daniel
authors.affiliation: School of Biomedical Science, The University of Queensland, Brisbane, Qld, 4072, Australia.
authors.forename: Han Siean
authors.initials: HS
authors.lastname: Lee
authors.affiliation: School of Biomedical Science, The University of Queensland, Brisbane, Qld, 4072, Australia.
authors.forename: Kathryn A V
authors.initials: KA
authors.lastname: Jackson
authors.affiliation: Health Innovations Research Institute, RMIT University, Melbourne, Vic, 3083, Australia.|Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, NSW, 2522, Australia.
authors.forename: Han-Shen
authors.initials: HS
authors.lastname: Tae
authors.affiliation: Health Innovations Research Institute, RMIT University, Melbourne, Vic, 3083, Australia.|Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, NSW, 2522, Australia.
authors.forename: Mahsa
authors.initials: M
authors.lastname: Sadeghi
authors.affiliation: Visceral Pain Group, Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, The University of Adelaide, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, 5000, Australia.
authors.forename: Joel
authors.initials: J
authors.lastname: Castro
authors.affiliation: Visceral Pain Group, Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, The University of Adelaide, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, 5000, Australia.
authors.forename: Tracy
authors.initials: T
authors.lastname: O'Donnell
authors.affiliation: Visceral Pain Group, Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, The University of Adelaide, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, 5000, Australia.
authors.forename: Annemie
authors.initials: A
authors.lastname: Deiteren
authors.affiliation: Visceral Pain Group, Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, The University of Adelaide, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, 5000, Australia.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Brierley
authors.affiliation: Institute for Molecular Biosciences, The University of Queensland, Brisbane, Qld, 4072, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Craik
authors.affiliation: Health Innovations Research Institute, RMIT University, Melbourne, Vic, 3083, Australia.|Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, NSW, 2522, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.affiliation: School of Biomedical Science, The University of Queensland, Brisbane, Qld, 4072, Australia. richard.clark@uq.edu.au.
authors.forename: Richard J
authors.identifier: http://orcid.org/0000-0002-6807-5426
authors.initials: RJ
authors.lastname: Clark
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020916:Conotoxins / Q000737:chemistry* / Q000494:pharmacology; D003545:Cysteine / Q000032:analysis*; D006801:Humans; D018080:Receptors, GABA-B / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D014981:Xenopus
chemical_list: D002121:Calcium Channel Blockers; D020916:Conotoxins; D018080:Receptors, GABA-B; D003545:Cysteine
keywords: analgesics; calcium channel; drug design; peptides; structure-activity relationships