Oral Presentation 10th Australian Peptide Conference 2013

Exploring bioactive peptides as pharmacological tools for oxytocin and vasopressin ligand design (#42)

Johannes Koehbach 1 , Margaret O'Brien 2 , Muharram Akcan 3 , David J Craik 3 , Markus Muttenthaler 4 , Christian W Gruber 1
  1. Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
  2. National Center for Biomedical and Engineering Science, National University of Ireland, Galway, Ireland
  3. Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
  4. Institute for Research in Biomedicine, Barcelona, Spain

The diversity in nature has long been and still is one of the biggest resources of pharmaceutical lead compounds and many natural products often exhibit biological activity against unrelated biological targets,1  thus providing us with starting points for pharmacological analysis. Natural peptides of great number and diversity occur in all organisms from plants to microbes to man. Examples for such rich and yet largely untapped libraries of bioactive compounds are animal venom peptides, invertebrate peptide hormones or plant defense peptides. Our goals are to discover and characterize novel bioactive peptides,4  screen their pharmacological activity, determine their structure-activity relationship and synthesize optimized peptide compounds to study ligand-receptor signaling.3

As proof-of-concept we have used a genome-mining approach or mass spectrometry to determine the occurrence and molecular structure of naturally-occurring oxytocin-like peptides and we have investigated their pharmacological profile on human oxytocin and vasopressin receptors. Plant cyclotides, insect inotocins2  and marine cone-snail conopressins5  have been identified as pharmacological probes to study receptor-subtype selectivity. Combining structure-activity analysis and peptide chemistry, we are aiming to generate selective, potent and stable peptide ligands that are potentially oral bioavailable and may be useful for the treatment of a wide range of challenging, but yet untreated diseases.

  1. Gruber CW, Muttenthaler M, Freissmuth M. Ligand-based peptide design and combinatorial peptide libraries to target G protein-coupled receptors. Curr Pharm Des. 2010; 16: 3071-3088.
  2. Gruber CW, Muttenthaler M. Discovery of defense- and neuropeptides in social ants by genome-mining. PLoS One. 2012; 7(3): e32559.
  3. Koehbach J, Stockner T, Bergmayr C, Muttenthaler M, Gruber CW. Insights into the molecular evolution of oxytocin receptor ligand binding. Biochem Soc Trans. 2013; 41: 197-204.
  4. Gruber CW, Koehbach J, Muttenthaler M. Exploring bioactive peptides from natural sources for oxytocin and vasopressin drug discovery. Future Med Chem. 2012; 4: 1791-1798.
  5. Dutertre S, Croker D, Daly NL, Andersson A, Muttenthaler M, Lumsden NG, Craik DJ, Alewood PF, Guillon G, Lewis RJ. Conopressin-T from Conus tulipa reveals an antagonist switch in vasopressin-like peptides. J Biol Chem. 2008; 283: 7100-7108.