title: Structurally minimized mu-conotoxin analogues as sodium channel blockers: implications for designing conopeptide-based therapeutics.
abstract: Disulfide bridges that stabilize the native conformation of conotoxins pose a challenge in the synthesis of smaller conotoxin analogues. Herein we describe the synthesis of a minimized analogue of the analgesic mu-conotoxin KIIIA that blocks two sodium channel subtypes, the neuronal Na(V)1.2 and skeletal muscle Na(V)1.4. Three disulfide-deficient analogues of KIIIA were initially synthesized in which the native disulfide bridge formed between either C1-C9, C2-C15, or C4-C16 was removed. Deletion of the first bridge only slightly affected the peptide's bioactivity. To further minimize this analogue, the N-terminal residue was removed and two nonessential serine residues were replaced by a single 5-amino-3-oxapentanoic acid residue. The resulting "polytide" analogue retained the ability to block sodium channels and to produce analgesia. Until now, the peptidomimetic approach applied to conotoxins has progressed only modestly at best; thus, the disulfide-deficient analogues containing backbone spacers provide an alternative advance toward the development of conopeptide-based therapeutics.
authors.affiliation: Department of Biology, University of Utah, 257 S 1400 E, Salt Lake City, UT 84112, USA.
authors.forename: Tiffany S
authors.initials: TS
authors.lastname: Han
authors.forename: Min-Min
authors.initials: MM
authors.lastname: Zhang
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Walewska
authors.forename: Pawel
authors.initials: P
authors.lastname: Gruszczynski
authors.forename: Charles R
authors.initials: CR
authors.lastname: Robertson
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Cheatham
authors.forename: Doju
authors.initials: D
authors.lastname: Yoshikami
authors.forename: Baldomero M
authors.initials: BM
authors.lastname: Olivera
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Bulaj
mesh_terms: D000595:Amino Acid Sequence; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003198:Computer Simulation; D020916:Conotoxins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004220:Disulfides / Q000138:chemical synthesis / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017510:Protein Folding; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D026941:Sodium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015222:Sodium Channels / Q000378:metabolism; D014981:Xenopus
chemical_list: D000700:Analgesics; D020916:Conotoxins; D004220:Disulfides; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C502265:mu-conotoxin KIIIA, Conus kinoshitai