Oxytocic plant cyclotides as templates for peptide G protein-coupled receptor ligand design

Koehbach, Johannes, O'Brien, Margaret, Muttenthaler, Markus, Miazzo, Marion, Akcan, Muharrem, Elliott, Alysha G., Daly, Norelle L., Harvey, Peta J., Arrowsmith, Sarah, Gunasekera, Sunithi, Smith, Terry J., Wray, Susan, Göransson, Ulf, Dawson, Philip E., Craik, David J., Freissmuth, Michael, and Gruber, Christian W. (2013) Oxytocic plant cyclotides as templates for peptide G protein-coupled receptor ligand design. Proceedings of the National Academy of Sciences of the United States of America, 110 (52). pp. 21183-21188.

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Cyclotides are plant peptides comprising a circular backbone and three conserved disulfide bonds that confer them with exceptional stability. They were originally discovered in Oldenlandia affinis based on their use in traditional African medicine to accelerate labor. Recently, cyclotides have been identified in numerous plant species of the coffee, violet, cucurbit, pea, potato, and grass families. Their unique structural topology, high stability, and tolerance to sequence variation make them promising templates for the development of peptide-based pharmaceuticals. However, the mechanisms underlying their biological activities remain largely unknown; specifically, a receptor for a native cyclotide has not been reported hitherto. Using bioactivity-guided fractionation of an herbal peptide extract known to indigenous healers as "kalata-kalata," the cyclotide kalata B7 was found to induce strong contractility on human uterine smooth muscle cells. Radioligand displacement and second messenger-based reporter assays confirmed the oxytocin and vasopressin V1a receptors, members of the G protein-coupled receptor family, as molecular targets for this cyclotide. Furthermore, we show that cyclotides can serve as templates for the design of selective G protein-coupled receptor ligands by generating an oxytocin-like peptide with nanomolar affinity. This nonapeptide elicited dose-dependent contractions on human myometrium. These observations provide a proof of concept for the development of cyclotide-based peptide ligands.

Item ID: 31677
Item Type: Article (Research - C1)
ISSN: 1091-6490
Keywords: circular plant peptide, peptide ligand design, uterotonic, chemical pharmacology, peptide drugs
Funders: Austrian Science Fund, European Union Seventh Framework Programme, Australian Research Council (ARC), National Health and Medical Research Council (NHMRC)
Projects and Grants: Austrian Science Fund Grant P22889-B11, European Union Seventh Framework Programme (FP7/2007-2013) Grant Agreement 254897
Date Deposited: 26 Feb 2014 09:35
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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