Transforming conotoxins into cyclotides: backbone cyclization of P-superfamily conotoxins

Akcan, Muharrem, Clark, Richard J., Daly, Norelle L., Conibear, Anne C., de Faoite, Andrew, Heghinian, Mari D., Sahil, Talwar, Adams, David J., Mari, Frank and Craik, David J. (2015) Transforming conotoxins into cyclotides: backbone cyclization of P-superfamily conotoxins. Peptide Science, 104 6: 682-692. doi:10.1002/bip.22699

Author Akcan, Muharrem
Clark, Richard J.
Daly, Norelle L.
Conibear, Anne C.
de Faoite, Andrew
Heghinian, Mari D.
Sahil, Talwar
Adams, David J.
Mari, Frank
Craik, David J.
Title Transforming conotoxins into cyclotides: backbone cyclization of P-superfamily conotoxins
Journal name Peptide Science   Check publisher's open access policy
ISSN 1097-0282
Publication date 2015-11-26
Sub-type Article (original research)
DOI 10.1002/bip.22699
Open Access Status Not Open Access
Volume 104
Issue 6
Start page 682
End page 692
Total pages 11
Place of publication Hoboken, NJ, United States
Publisher John Wiley & Sons
Language eng
Abstract Peptide backbone cyclization is a widely used approach to improve the activity and stability of small peptides but until recently had not been applied to peptides with multiple disulfide bonds. Conotoxins are disulfide-rich conopeptides derived from the venoms of cone snails that have applications in drug design and development. However, because of their peptidic nature, they can suffer from poor bioavailability and poor stability in vivo. In this study two P-superfamily conotoxins, gm9a and bru9a, were backbone cyclised by joining the N- and C-termini with short peptide linkers using intramolecular native chemical ligation chemistry. The cyclised derivatives had conformations similar to the native peptides showing that backbone cyclization can be applied to three disulfide-bonded peptides with cystine knot motifs. Cyclic gm9a was more potent at high voltage-activated (HVA) calcium channels than its acyclic counterpart, highlighting the value of this approach in developing active and stable conotoxins containing cyclic cystine knot motifs.
Keyword Conotoxins
Cyclic peptide
Cystine knot
Drug design
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2016 Collection
Institute for Molecular Bioscience - Publications
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Created: Fri, 18 Sep 2015, 23:04:17 EST by Susan Allen on behalf of Office of the Vice-Chancellor