Cyclic MrIA: A stable and potent cyclic conotoxin with a novel topological fold that targets the norepinephrine transporter

Lovelace, E. S., Armishaw, C. J., Colgrave, M. L., Wahlstrom, M. E., Alewood, P. F., Daly, N. L. and Craik, D. J. (2006) Cyclic MrIA: A stable and potent cyclic conotoxin with a novel topological fold that targets the norepinephrine transporter. Journal of Medicinal Chemistry, 49 22: 6561-6568. doi:10.1021/jm060299h


Author Lovelace, E. S.
Armishaw, C. J.
Colgrave, M. L.
Wahlstrom, M. E.
Alewood, P. F.
Daly, N. L.
Craik, D. J.
Title Cyclic MrIA: A stable and potent cyclic conotoxin with a novel topological fold that targets the norepinephrine transporter
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0022-2623
Publication date 2006
Sub-type Article (original research)
DOI 10.1021/jm060299h
Volume 49
Issue 22
Start page 6561
End page 6568
Total pages 8
Editor Philip S. Portoghese
Place of publication Washington, D. C.
Publisher American Chemical Society
Collection year 2006
Language eng
Subject C1
250302 Biological and Medical Chemistry
780105 Biological sciences
Abstract 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.
Keyword Conotoxins
Pain Treatment
Chemistry, Medicinal
Native Chemical Ligation
Trypsin-inhibitor Sfti-1
Cystine Knot
Alpha-conotoxins
Neuropathic Pain
Chi-conopeptide
Conus-marmoreus
Sunflower Seeds
Kalata B1
Peptide
Q-Index Code C1

 
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Created: Wed, 15 Aug 2007, 08:35:23 EST