title: Structure and activity of (2,8)-dicarba-(3,12)-cystino alpha-ImI, an alpha-conotoxin containing a nonreducible cystine analogue.
abstract: The alpha-conotoxins are potent and selective antagonists of nicotinic acetylcholine receptors (nAChR). Exploitation of these and other peptides in research and clinical settings has been hampered by the lability of the disulfide bridges that are essential for toxin structure and activity. One solution to this problem is replacement of cystine bridges with nonreducible dicarba linkages. We explore this approach by determining the solution structure and functional characteristics of a dicarba analogue of the alpha-conotoxin alpha-ImI, (2,8)-dicarba-(3,12)-cystino alpha-ImI. The structure of the dicarba analogue was similar to that of native alpha-ImI, with differences attributable to the different covalent geometry of the disulfide and dicarba bridges. Dicarba-alpha-ImI maintained inhibitory activity of nAChR comparable to that of native alpha-ImI in two in vitro assays. These findings confirm the potential of the dicarba linkage to improve stability while maintaining alpha-conotoxin function.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3050, Victoria, Australia.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: MacRaild
authors.forename: Jayamini
authors.initials: J
authors.lastname: Illesinghe
authors.forename: Bianca J
authors.initials: BJ
authors.lastname: van Lierop
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Townsend
authors.forename: Mary
authors.initials: M
authors.lastname: Chebib
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Livett
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Robinson
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Norton
mesh_terms: D000818:Animals; D002417:Cattle; D019439:Chromaffin Cells / Q000187:drug effects; D020916:Conotoxins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects
chemical_list: C538799:(2,8)-dicarba-(3,12)-cystino alpha-ImI; D020916:Conotoxins; D011978:Receptors, Nicotinic