Selenoether oxytocin analogues have analgesic properties in a mouse model of chronic abdominal pain

Aline Dantas de Araujo, Mehdi Mobli, Joel Castro, Andrea M. Harrington, Irina Vetter, Zoltan Dekan, Markus Muttenthaler, JingJing Wan, Richard J. Lewis, Glenn F. King, Stuart M. Brierley () and Paul F. Alewood ()
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Aline Dantas de Araujo: Institute for Molecular Bioscience, The University of Queensland
Mehdi Mobli: Institute for Molecular Bioscience, The University of Queensland
Joel Castro: Nerve-Gut Research Laboratory, Discipline of Medicine, The University of Adelaide
Andrea M. Harrington: Nerve-Gut Research Laboratory, Discipline of Medicine, The University of Adelaide
Irina Vetter: Institute for Molecular Bioscience, The University of Queensland
Zoltan Dekan: Institute for Molecular Bioscience, The University of Queensland
Markus Muttenthaler: Institute for Molecular Bioscience, The University of Queensland
JingJing Wan: Institute for Molecular Bioscience, The University of Queensland
Richard J. Lewis: Institute for Molecular Bioscience, The University of Queensland
Glenn F. King: Institute for Molecular Bioscience, The University of Queensland
Stuart M. Brierley: Nerve-Gut Research Laboratory, Discipline of Medicine, The University of Adelaide
Paul F. Alewood: Institute for Molecular Bioscience, The University of Queensland

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: Abstract Poor oral availability and susceptibility to reduction and protease degradation is a major hurdle in peptide drug development. However, drugable receptors in the gut present an attractive niche for peptide therapeutics. Here we demonstrate, in a mouse model of chronic abdominal pain, that oxytocin receptors are significantly upregulated in nociceptors innervating the colon. Correspondingly, we develop chemical strategies to engineer non-reducible and therefore more stable oxytocin analogues. Chemoselective selenide macrocyclization yields stabilized analogues equipotent to native oxytocin. Ultra-high-field nuclear magnetic resonance structural analysis of native oxytocin and the seleno-oxytocin derivatives reveals that oxytocin has a pre-organized structure in solution, in marked contrast to earlier X-ray crystallography studies. Finally, we show that these seleno-oxytocin analogues potently inhibit colonic nociceptors both in vitro and in vivo in mice with chronic visceral hypersensitivity. Our findings have potentially important implications for clinical use of oxytocin analogues and disulphide-rich peptides in general.

Date: 2014
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DOI: 10.1038/ncomms4165

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