title: Dicarba α-conotoxin Vc1.1 analogues with differential selectivity for nicotinic acetylcholine and GABAB receptors.
abstract: Conotoxins have emerged as useful leads for the development of novel therapeutic analgesics. These peptides, isolated from marine molluscs of the genus Conus, have evolved exquisite selectivity for receptors and ion channels of excitable tissue. One such peptide, α-conotoxin Vc1.1, is a 16-mer possessing an interlocked disulfide framework. Despite its emergence as a potent analgesic lead, the molecular target and mechanism of action of Vc1.1 have not been elucidated to date. In this paper we describe the regioselective synthesis of dicarba analogues of Vc1.1 using olefin metathesis. The ability of these peptides to inhibit acetylcholine-evoked current at rat α9α10 and α3β4 nicotinic acetylcholine receptors (nAChR) expressed in Xenopus oocytes has been assessed in addition to their ability to inhibit high voltage-activated (HVA) calcium channel current in isolated rat DRG neurons. Their solution structures were determined by NMR spectroscopy. Significantly, we have found that regioselective replacement of the native cystine framework with a dicarba bridge can be used to selectively tune the cyclic peptide's innate biological activity for one receptor over another. The 2,8-dicarba Vc1.1 isomer retains activity at γ-aminobutyric acid (GABAB) G protein-coupled receptors, whereas the isomeric 3,16-dicarba Vc1.1 peptide retains activity at the α9α10 nAChR subtype. These singularly acting analogues will enable the elucidation of the biological target responsible for the peptide's potent analgesic activity.
authors.affiliation: School of Chemistry, Monash University, Clayton 3800, Victoria, Australia.
authors.forename: Bianca J
authors.initials: BJ
authors.lastname: van Lierop
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Robinson
authors.forename: Shiva N
authors.initials: SN
authors.lastname: Kompella
authors.forename: Alessia
authors.initials: A
authors.lastname: Belgi
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: McArthur
authors.forename: Andrew
authors.initials: A
authors.lastname: Hung
authors.forename: Christopher A
authors.initials: CA
authors.lastname: MacRaild
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Norton
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Robinson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020916:Conotoxins / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008954:Models, Biological; D009474:Neurons / Q000737:chemistry / Q000187:drug effects; D009865:Oocytes / Q000737:chemistry / Q000187:drug effects; D051381:Rats; D018079:Receptors, GABA / Q000737:chemistry*; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000235:genetics; D014981:Xenopus / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000737:chemistry
chemical_list: D020916:Conotoxins; D018079:Receptors, GABA; D011978:Receptors, Nicotinic; D005680:gamma-Aminobutyric Acid; C507383:alpha-conotoxin Vc1.1