2MFY: Non-reducible analogues of alpha-conotoxin Vc1.1: [2,8]-trans dicarba Vc1.1

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, alpha-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 alpha9alpha10 and alpha3beta4 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 gamma-aminobutyric acid (GABAB) G protein-coupled receptors, whereas the isomeric 3,16-dicarba Vc1.1 peptide retains activity at the alpha9alpha10 nAChR subtype. These singularly acting analogues will enable the elucidation of the biological target responsible for the peptide's potent analgesic activity.
PDB ID: 2MFYDownload
MMDB ID: 115981
PDB Deposition Date: 2013/10/24
Updated in MMDB: 2013/12
Experimental Method:
solution nmr
Similar Structures:
Biological Unit for 2MFY: monomeric; determined by author
Molecular Components in 2MFY
Label Count Molecule
Protein (1 molecule)
Alpha-conotoxin Vc1a
Molecule annotation
* Click molecule labels to explore molecular sequence information.

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