Dicarba α-conotoxin Vc1.1 analogues with differential selectivity for nicotinic acetylcholine and GABAB receptors

Van Lierop, Bianca J., Robinson, Samuel D., Kompella, Shiva N., Belgi, Alessia, McArthur, Jeffrey R., Hung, Andrew, Macraild, Christopher A., Adams, David J., Norton, Raymond S. and Robinson, Andrea J. (2013) Dicarba α-conotoxin Vc1.1 analogues with differential selectivity for nicotinic acetylcholine and GABAB receptors. ACS Chemical Biology, 8 8: 1815-1821. doi:10.1021/cb4002393


Author Van Lierop, Bianca J.
Robinson, Samuel D.
Kompella, Shiva N.
Belgi, Alessia
McArthur, Jeffrey R.
Hung, Andrew
Macraild, Christopher A.
Adams, David J.
Norton, Raymond S.
Robinson, Andrea J.
Title Dicarba α-conotoxin Vc1.1 analogues with differential selectivity for nicotinic acetylcholine and GABAB receptors
Formatted title
Dicarba α-conotoxin Vc1.1 analogues with differential selectivity for nicotinic acetylcholine and GABAB receptors
Journal name ACS Chemical Biology   Check publisher's open access policy
ISSN 1554-8929
1554-8937
Publication date 2013-08-16
Sub-type Article (original research)
DOI 10.1021/cb4002393
Open Access Status
Volume 8
Issue 8
Start page 1815
End page 1821
Total pages 7
Place of publication Washington, United States
Publisher American Chemical Society
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Queensland Brain Institute Publications
 
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Created: Mon, 27 Oct 2014, 17:59:46 EST by Sylvie Pichelin on behalf of Queensland Brain Institute