| Structural highlights
Function
CA1A_CONVC Alpha-conotoxins act on postsynaptic membranes, they bind to the nicotinic acetylcholine receptors (nAChR) and thus inhibit them. This synthetic peptide (produced without hydroxyproline, nor 4-carboxyglutamate) is a neuronal nAChR antagonist that acts as a powerful analgesic. It blocks nAChRs composed of alpha-3 or -5/beta-2 (IC(50)=7.2 uM), alpha-3/beta-2 (IC(50)=7.3 uM), alpha-3/beta-4 (IC(50)=4.2 uM), alpha-3 or -5/beta-4 (IC(50)<30 uM), alpha-4/beta-2 (IC(50)<30 uM), alpha-4/beta-4 (IC(50)<30 uM) and alpha/beta/gamma/delta (IC(50)<30 uM) subunits.[1] [2]
Publication Abstract from PubMed
Several Conus-derived venom peptides are promising lead compounds for the management of neuropathic pain, with alpha-conotoxins being of particular interest. Modification of the interlocked disulfide framework of alpha-conotoxin Vc1.1 has been achieved using on-resin alkyne metathesis. Although introduction of a metabolically stable alkyne motif significantly disrupts backbone topography, the structural modification generates a potent and selective GABAB receptor agonist that inhibits Cav2.2 channels and exhibits dose-dependent reversal of mechanical allodynia in a behavioral rat model of neuropathic pain. The findings herein support the hypothesis that analgesia can be achieved via activation of GABABRs expressed in dorsal root ganglion (DRG) sensory neurons.
Alkyne-Bridged alpha-Conotoxin Vc1.1 Potently Reverses Mechanical Allodynia in Neuropathic Pain Models.,Belgi A, Burnley JV, MacRaild CA, Chhabra S, Elnahriry KA, Robinson SD, Gooding SG, Tae HS, Bartels P, Sadeghi M, Zhao FY, Wei H, Spanswick D, Adams DJ, Norton RS, Robinson AJ J Med Chem. 2021 Mar 25;64(6):3222-3233. doi: 10.1021/acs.jmedchem.0c02151. Epub , 2021 Mar 16. PMID:33724033[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Sandall DW, Satkunanathan N, Keays DA, Polidano MA, Liping X, Pham V, Down JG, Khalil Z, Livett BG, Gayler KR. A novel alpha-conotoxin identified by gene sequencing is active in suppressing the vascular response to selective stimulation of sensory nerves in vivo. Biochemistry. 2003 Jun 10;42(22):6904-11. PMID:12779345 doi:http://dx.doi.org/10.1021/bi034043e
- ↑ Lang PM, Burgstahler R, Haberberger RV, Sippel W, Grafe P. A conus peptide blocks nicotinic receptors of unmyelinated axons in human nerves. Neuroreport. 2005 Apr 4;16(5):479-83. PMID:15770155
- ↑ Belgi A, Burnley JV, MacRaild CA, Chhabra S, Elnahriry KA, Robinson SD, Gooding SG, Tae HS, Bartels P, Sadeghi M, Zhao FY, Wei H, Spanswick D, Adams DJ, Norton RS, Robinson AJ. Alkyne-Bridged α-Conotoxin Vc1.1 Potently Reverses Mechanical Allodynia in Neuropathic Pain Models. J Med Chem. 2021 Mar 25;64(6):3222-3233. PMID:33724033 doi:10.1021/acs.jmedchem.0c02151
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