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

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Overview

authors

  • Koehbach, J.
  • O'Brien, M.
  • Muttenthaler, M.
  • Miazzo, M.
  • Akcan, M.
  • Elliott, A. G.
  • Daly, N. L.
  • Harvey, P. J.
  • Arrowsmith, S.
  • Gunasekera, S.
  • Smith, T. J.
  • Wray, S.
  • Goransson, U.
  • Dawson, Philip
  • Craik, D. J.
  • Freissmuth, M.
  • Gruber, C. W.

publication date

  • December 2013

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • 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.

subject areas

  • Analysis of Variance
  • Chromatography, High Pressure Liquid
  • Cloning, Molecular
  • Collagen
  • Cyclotides
  • Drug Design
  • Female
  • Humans
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Oldenlandia
  • Oligopeptides
  • Oxytocics
  • Radioligand Assay
  • Receptors, G-Protein-Coupled
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Uterine Contraction
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Research

keywords

  • chemical pharmacology
  • circular plant peptide
  • peptide drugs
  • peptide ligand design
  • uterotonic
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Identity

PubMed Central ID

  • PMC3876230

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.1311183110

PubMed ID

  • 24248349
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Additional Document Info

start page

  • 21183

end page

  • 21188

volume

  • 110

issue

  • 52

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