| Structural highlights
Function
CTA1A_CONMR Chi-conotoxins inhibit the neuronal noradrenaline transporter (NET/SLC6A2) (PubMed:11528421, PubMed:12837768, PubMed:12885787, PubMed:16154696). Activity has been described on both human (inhibition of norepinephrine uptake is IC(50)=1.26 uM) and rat (pIC(50)=6.21 corresponding IC(50)=0.16 uM) transporters (PubMed:11528421, PubMed:12885787). Acts as a reversible non-competitive inhibitor (PubMed:11528421).[1] [2] [3] [4]
Publication Abstract from PubMed
Conotoxins, disulfide-rich peptides from the venom of cone snails, have created much excitement over recent years due to their potency and specificity for ion channels and their therapeutic potential. One recently identified conotoxin, MrIA, a 13-residue member of the chi-conotoxin family, inhibits the human norepinephrine transporter (NET) and has potential applications in the treatment of pain. In the current study, we show that the beta-hairpin structure of native MrIA is retained in a synthetic cyclic version, as is biological activity at the NET. Furthermore, the cyclic version has increased resistance to trypsin digestion relative to the native peptide, an intriguing result because the cleavage site for the trypsin is not close to the cyclization site. The use of peptides as drugs is generally hampered by susceptibility to proteolysis, and so, the increase in enzymatic stability against trypsin observed in the current study may be useful in improving the therapeutic potential of MrIA. Furthermore, the structure reported here for cyclic MrIA represents a new topology among a growing number of circular disulfide-rich peptides.
Cyclic MrIA: a stable and potent cyclic conotoxin with a novel topological fold that targets the norepinephrine transporter.,Lovelace ES, Armishaw CJ, Colgrave ML, Wahlstrom ME, Alewood PF, Daly NL, Craik DJ J Med Chem. 2006 Nov 2;49(22):6561-8. PMID:17064074[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Sharpe IA, Gehrmann J, Loughnan ML, Thomas L, Adams DA, Atkins A, Palant E, Craik DJ, Adams DJ, Alewood PF, Lewis RJ. Two new classes of conopeptides inhibit the alpha1-adrenoceptor and noradrenaline transporter. Nat Neurosci. 2001 Sep;4(9):902-7. PMID:11528421 doi:http://dx.doi.org/10.1038/nn0901-902
- ↑ Bryan-Lluka LJ, Bonisch H, Lewis RJ. chi-Conopeptide MrIA partially overlaps desipramine and cocaine binding sites on the human norepinephrine transporter. J Biol Chem. 2003 Oct 10;278(41):40324-9. Epub 2003 Jul 1. PMID:12837768 doi:http://dx.doi.org/10.1074/jbc.M213101200
- ↑ Sharpe IA, Palant E, Schroeder CI, Kaye DM, Adams DJ, Alewood PF, Lewis RJ. Inhibition of the norepinephrine transporter by the venom peptide chi-MrIA. Site of action, Na+ dependence, and structure-activity relationship. J Biol Chem. 2003 Oct 10;278(41):40317-23. Epub 2003 Jul 28. PMID:12885787 doi:http://dx.doi.org/10.1074/jbc.M213030200
- ↑ Nielsen CK, Lewis RJ, Alewood D, Drinkwater R, Palant E, Patterson M, Yaksh TL, McCumber D, Smith MT. Anti-allodynic efficacy of the chi-conopeptide, Xen2174, in rats with neuropathic pain. Pain. 2005 Nov;118(1-2):112-24. Epub 2005 Sep 9. PMID:16154696 doi:http://dx.doi.org/S0304-3959(05)00384-2
- ↑ Lovelace ES, Armishaw CJ, Colgrave ML, Wahlstrom ME, Alewood PF, Daly NL, Craik DJ. Cyclic MrIA: a stable and potent cyclic conotoxin with a novel topological fold that targets the norepinephrine transporter. J Med Chem. 2006 Nov 2;49(22):6561-8. PMID:17064074 doi:http://dx.doi.org/10.1021/jm060299h
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