| Structural highlights
Function
CA12_CONMA Alpha-conotoxins bind to the nicotinic acetylcholine receptors (nAChR) and inhibit them. This toxin blocks neuronal mammalian nAChRs (alpha-6/alpha-3-beta-2-beta-3 (0.39 nM) > alpha-3-beta-2/CHRNA3-CHRNB2 > alpha-3-beta-4/CHRNA3-CHRNB4 = alpha-4-beta-2/CHRNA4-CHRNB2) (PubMed:15005608, PubMed:20145249). Also exhibits inhibition of D.melanogaster alpha-7/CHRNA7 nAChRs (PubMed:25466886). In addition, inhibits alpha-6/alpha-3-beta-4 (CHRNA6/CHRNA3-CHRNB4) nAChR with a higher potency on human (IC(50)=1.49 nM) than on rat receptors (IC(50)=31.5 nM) (PubMed:33523678). Its binding to alpha-3-beta-2/CHRNA3-CHRNB2 nAChR is prevented by alpha-conotoxin Lt1a, suggesting that the two toxins have overlapping binding sites (PubMed:20145249). In addition, both toxins have distinct nAChR binding mode (PubMed:20145249). In vivo, inhibits Ehrlich carcinoma growth and increase mouse survival (PubMed:32272633). These effects are greatly enhanced when the toxin is applied with the non-selective cyclooxygenase inhibitor indomethacin (PubMed:32272633).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10]
Publication Abstract from PubMed
Conotoxins (CTXs), with their exquisite specificity and potency, have recently created much excitement as drug leads. However, like most peptides, their beneficial activities may potentially be undermined by susceptibility to proteolysis in vivo. By cyclizing the alpha-CTX MII by using a range of linkers, we have engineered peptides that preserve their full activity but have greatly improved resistance to proteolytic degradation. The cyclic MII analogue containing a seven-residue linker joining the N and C termini was as active and selective as the native peptide for native and recombinant neuronal nicotinic acetylcholine receptor subtypes present in bovine chromaffin cells and expressed in Xenopus oocytes, respectively. Furthermore, its resistance to proteolysis against a specific protease and in human plasma was significantly improved. More generally, to our knowledge, this report is the first on the cyclization of disulfide-rich toxins. Cyclization strategies represent an approach for stabilizing bioactive peptides while keeping their full potencies and should boost applications of peptide-based drugs in human medicine.
Engineering stable peptide toxins by means of backbone cyclization: stabilization of the alpha-conotoxin MII.,Clark RJ, Fischer H, Dempster L, Daly NL, Rosengren KJ, Nevin ST, Meunier FA, Adams DJ, Craik DJ Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):13767-72. Epub 2005 Sep 14. PMID:16162671[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kuryatov A, Olale F, Cooper J, Choi C, Lindstrom J. Human alpha6 AChR subtypes: subunit composition, assembly, and pharmacological responses. Neuropharmacology. 2000 Oct;39(13):2570-90. PMID:11044728
- ↑ Everhart D, Cartier GE, Malhotra A, Gomes AV, McIntosh JM, Luetje CW. Determinants of potency on alpha-conotoxin MII, a peptide antagonist of neuronal nicotinic receptors. Biochemistry. 2004 Mar 16;43(10):2732-7. PMID:15005608 doi:10.1021/bi036180h
- ↑ McIntosh JM, Azam L, Staheli S, Dowell C, Lindstrom JM, Kuryatov A, Garrett JE, Marks MJ, Whiteaker P. Analogs of alpha-conotoxin MII are selective for alpha6-containing nicotinic acetylcholine receptors. Mol Pharmacol. 2004 Apr;65(4):944-52. PMID:15044624 doi:10.1124/mol.65.4.944
- ↑ Dutertre S, Nicke A, Lewis RJ. Beta2 subunit contribution to 4/7 alpha-conotoxin binding to the nicotinic acetylcholine receptor. J Biol Chem. 2005 Aug 26;280(34):30460-8. Epub 2005 Jun 1. PMID:15929983 doi:http://dx.doi.org/10.1074/jbc.M504229200
- ↑ Shiembob DL, Roberts RL, Luetje CW, McIntosh JM. Determinants of alpha-conotoxin BuIA selectivity on the nicotinic acetylcholine receptor beta subunit. Biochemistry. 2006 Sep 19;45(37):11200-7. PMID:16964981 doi:10.1021/bi0611715
- ↑ Luo S, Akondi KB, Zhangsun D, Wu Y, Zhu X, Hu Y, Christensen S, Dowell C, Daly NL, Craik DJ, Wang CI, Lewis RJ, Alewood PF, Michael McIntosh J. Atypical alpha-conotoxin LtIA from Conus litteratus targets a novel microsite of the alpha3beta2 nicotinic receptor. J Biol Chem. 2010 Apr 16;285(16):12355-66. PMID:20145249 doi:10.1074/jbc.M109.079012
- ↑ Heghinian MD, Mejia M, Adams DJ, Godenschwege TA, Marí F. Inhibition of cholinergic pathways in Drosophila melanogaster by α-conotoxins. FASEB J. 2015 Mar;29(3):1011-8. PMID:25466886 doi:10.1096/fj.14-262733
- ↑ Osipov AV, Terpinskaya TI, Yanchanka T, Balashevich T, Zhmak MN, Tsetlin VI, Utkin YN. α-Conotoxins Enhance both the In Vivo Suppression of Ehrlich carcinoma Growth and In Vitro Reduction in Cell Viability Elicited by Cyclooxygenase and Lipoxygenase Inhibitors. Mar Drugs. 2020 Apr 7;18(4):193. PMID:32272633 doi:10.3390/md18040193
- ↑ Hone AJ, Kaas Q, Kearns I, Hararah F, Gajewiak J, Christensen S, Craik DJ, McIntosh JM. Computational and Functional Mapping of Human and Rat α6β4 Nicotinic Acetylcholine Receptors Reveals Species-Specific Ligand-Binding Motifs. J Med Chem. 2021 Feb 11;64(3):1685-1700. PMID:33523678 doi:10.1021/acs.jmedchem.0c01973
- ↑ Cartier GE, Yoshikami D, Gray WR, Luo S, Olivera BM, McIntosh JM. A new alpha-conotoxin which targets alpha3beta2 nicotinic acetylcholine receptors. J Biol Chem. 1996 Mar 29;271(13):7522-8. PMID:8631783
- ↑ Clark RJ, Fischer H, Dempster L, Daly NL, Rosengren KJ, Nevin ST, Meunier FA, Adams DJ, Craik DJ. Engineering stable peptide toxins by means of backbone cyclization: stabilization of the alpha-conotoxin MII. Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):13767-72. Epub 2005 Sep 14. PMID:16162671 doi:0504613102
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