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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.
Carstens, Bodil B; Berecki, Géza; Daniel, James T; Lee, Han Siean; Jackson, Kathryn A V; Tae, Han-Shen; Sadeghi, Mahsa; Castro, Joel; O'Donnell, Tracy; Deiteren, Annemie; Brierley, Stuart M; Craik, David J; Adams, David J; Clark, Richard J.
Affiliation
  • Carstens BB; Institute for Molecular Biosciences, The University of Queensland, Brisbane, Qld, 4072, Australia.
  • Berecki G; Health Innovations Research Institute, RMIT University, Melbourne, Vic, 3083, Australia.
  • Daniel JT; School of Biomedical Science, The University of Queensland, Brisbane, Qld, 4072, Australia.
  • Lee HS; School of Biomedical Science, The University of Queensland, Brisbane, Qld, 4072, Australia.
  • Jackson KA; School of Biomedical Science, The University of Queensland, Brisbane, Qld, 4072, Australia.
  • Tae HS; Health Innovations Research Institute, RMIT University, Melbourne, Vic, 3083, Australia.
  • Sadeghi M; Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, NSW, 2522, Australia.
  • Castro J; Health Innovations Research Institute, RMIT University, Melbourne, Vic, 3083, Australia.
  • O'Donnell T; Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, NSW, 2522, Australia.
  • Deiteren A; 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.
  • Brierley SM; 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.
  • Craik DJ; 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.
  • Adams DJ; 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.
  • Clark RJ; Institute for Molecular Biosciences, The University of Queensland, Brisbane, Qld, 4072, Australia.
Angew Chem Int Ed Engl ; 55(15): 4692-6, 2016 Apr 04.
Article in En | MEDLINE | ID: mdl-26948522
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Calcium Channel Blockers / Receptors, GABA-B / Conotoxins / Amino Acid Motifs / Cysteine Limits: Animals / Humans Language: En Journal: Angew Chem Int Ed Engl Year: 2016 Type: Article Affiliation country: Australia
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Calcium Channel Blockers / Receptors, GABA-B / Conotoxins / Amino Acid Motifs / Cysteine Limits: Animals / Humans Language: En Journal: Angew Chem Int Ed Engl Year: 2016 Type: Article Affiliation country: Australia