The anthelmintic activity of the cyclotides: Natural variants with enhanced activity

Colgrave, Michelle L., Kotze, Andrew C., Ireland, David C., Wang, Conan K. and Craik, David J. (2008) The anthelmintic activity of the cyclotides: Natural variants with enhanced activity. ChemBioChem, 9 12: 1939-1945. doi:10.1002/cbic.200800174


Author Colgrave, Michelle L.
Kotze, Andrew C.
Ireland, David C.
Wang, Conan K.
Craik, David J.
Title The anthelmintic activity of the cyclotides: Natural variants with enhanced activity
Journal name ChemBioChem   Check publisher's open access policy
ISSN 1439-4227
Publication date 2008-09-01
Year available 2008
Sub-type Article (original research)
DOI 10.1002/cbic.200800174
Open Access Status DOI
Volume 9
Issue 12
Start page 1939
End page 1945
Total pages 7
Editor Alan R. Fersht
Place of publication Weinheim, Germany
Publisher Wiley
Language eng
Subject C1
030401 Biologically Active Molecules
860701 Animal Protection Chemicals
Abstract The cyclotides are a family of backbone-cyclised cystine-knot-containing peptides from plants that possess anthelmintic activity against Haemonchus contortus and Trichostrongylus colubriformis, two important gastrointestinal nematode parasites of sheep. In the current study, we investigated the in vitro effects of newly discovered natural cyclotides on the viability of larval and adult life stages of these pests. The natural variants cycloviolacin O2, cycloviolacin O3, cycloviolacin O8, cycloviolocin O13, cycloviolocin O14, cycloviolacin O75, and cycloviolocin O16 extracted from Viola odorata showed up to 18-fold greater potency than the prototypic cyclotide kalata 67 in nematode larval development assays. Cycloviolacin O2 and cycloviolocin O14 were significantly more potent than kalata B7 in adult H. contortus motility assays. The lysine and glutamic acid residues of cycloviolacin O2, the most potent anthelmintic cyclotide, were chemically modified to investigate the role of these charged residues in modulating the biological activity. The single glutomic acid residue, which is conserved across all known cyclotides, was shown to be essential for activity, with a sixfold decrease in potency of cycloviolacin O2 following methylation. The three lysine residues present in cycloviolacin O2 were acetylated to effectively mask the positive charge, resulting in a 18-fold decrease in anthelmintic activity. The relative anthelmintic activities of the natural variants assayed against nematode larvae correlated with the number of charged residues present in their sequence.
Formatted abstract
The cyclotides are a family of backbone-cyclised cystine-knot-containing peptides from plants that possess anthelmintic activity against Haemonchus contortus and Trichostrongylus colubriformis, two important gastrointestinal nematode parasites of sheep. In the current study, we investigated the in vitro effects of newly discovered natural cyclotides on the viability of larval and adult life stages of these pests. The natural variants cycloviolacin O2, cycloviolacin O3, cycloviolacin O8, cycloviolacin O13, cycloviolacin O14, cycloviolacin O15, and cycloviolacin O16 extracted from Viola odorata showed up to 18-fold greater potency than the prototypic cyclotide kalata B1 in nematode larval development assays. Cycloviolacin O2 and cycloviolacin O14 were significantly more potent than kalata B1 in adult H. contortus motility assays. The lysine and glutamic acid residues of cycloviolacin O2, the most potent anthelmintic cyclotide, were chemically modified to investigate the role of these charged residues in modulating the biological activity. The single glutamic acid residue, which is conserved across all known cyclotides, was shown to be essential for activity, with a sixfold decrease in potency of cycloviolacin O2 following methylation. The three lysine residues present in cycloviolacin O2 were acetylated to effectively mask the positive charge, resulting in a 18-fold decrease in anthelmintic activity. The relative anthelmintic activities of the natural variants assayed against nematode larvae correlated with the number of charged residues present in their sequence.
Keyword anthelmintics
biological activity
cyclotides
peptides
protein modifications
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published Online: 11 Jul 2008

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2009 Higher Education Research Data Collection
School of Veterinary Science Publications
 
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Created: Thu, 16 Apr 2009, 00:22:09 EST by Jennifer Greder on behalf of Institute for Molecular Bioscience