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., Marí, Frank, and Craik, David J. (2015) Transforming conotoxins into cyclotides: backbone cyclization of P-superfamily conotoxins. Biopolymers, 104 (6). pp. 682-692.

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Peptide backbone cyclization is a widely used approach to improve the activity and stability of small peptides but until recently it 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 cyclized by joining the N- and C-termini with short peptide linkers using intramolecular native chemical ligation chemistry. The cyclized 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.

Item ID: 44419
Item Type: Article (Research - C1)
ISSN: 0006-3525
Keywords: conotoxins; cyclic peptide; cyclization; cystine knot; drug design
Funders: Australian Research Council (ARC), National Health and Medical Research Council (NHMRC)
Projects and Grants: ARC DP1093115, NHMRC APP1076136 and APP1026501, ARC Future Fellowship Project
Date Deposited: 17 Jun 2016 05:45
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1101 Medical Biochemistry and Metabolomics > 110106 Medical Biochemistry: Proteins and Peptides (incl Medical Proteomics) @ 100%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970111 Expanding Knowledge in the Medical and Health Sciences @ 100%
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