title: Effects of cyclization on stability, structure, and activity of α-conotoxin RgIA at the α9α10 nicotinic acetylcholine receptor and GABA(B) receptor.
abstract: α-Conotoxin RgIA is of interest as a lead in the development of drugs for neuropathic pain. It modulates the α9α10 nicotinic acetylcholine receptor (nAChR) and the GABA(B) receptor, both of which are implicated in antinociception. However, because of its peptidic nature, RgIA is potentially susceptible to generic problems encountered by peptide-based drugs of poor oral bioavailability, short biological half-life, and low stability. Here, we improved the biopharmaceutical properties of RgIA by backbone cyclization using 3-7 residue peptidic linkers. Cyclization with a six-residue linker does not perturb the overall structure of RgIA, improves selectivity for the GABA(B) receptor over the α9α10 nAChR, and improves stability in human serum. The results provide insights to further improve the therapeutic properties of RgIA and other conotoxins being considered as drug leads and confirm that cyclization is a readily applicable strategy to improve the stability of peptides with proximate N- and C-termini.
authors: Institute for Molecular Bioscience, Division of Chemistry and Structural Biology, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors: Reena
authors: R
authors: Halai
authors: Brid
authors: B
authors: Callaghan
authors: Norelle L
authors: NL
authors: Daly
authors: Richard J
authors: RJ
authors: Clark
authors: David J
authors: DJ
authors: Adams
authors: David J
authors: DJ
authors: Craik
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology; D020864:Calcium Channels, N-Type / Q000502:physiology; D020916:Conotoxins / Q000737:chemistry* / Q000494:pharmacology; D003500:Cyclization; D004355:Drug Stability; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D017510:Protein Folding; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000502:physiology*; D011978:Receptors, Nicotinic / Q000502:physiology*; D044967:Serum; D014981:Xenopus
chemical_list: D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; C470699:Chrna10 protein, rat; D020916:Conotoxins; D010456:Peptides, Cyclic; D011963:Receptors, GABA-A; D011978:Receptors, Nicotinic; C510079:conotoxin alpha-RgIA, Conus regius; C443079:nAChR alpha9