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

Dantas De Araujo, Aline, Mobli, Mehdi, Castro, Joel, Harrington, Andrea M., Vetter, Irina, Dekan, Zoltan, Muttenthale, Markus, Wan, JingJing, Lewis, Richard J., King, Glenn F., Brierley, Stuart M. and Alewood, Paul F. (2014) Selenoether oxytocin analogues have analgesic properties in a mouse model of chronic abdominal pain. Nature Communications, 5 3165.1-3165.12. doi:10.1038/ncomms4165

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Author Dantas De Araujo, Aline
Mobli, Mehdi
Castro, Joel
Harrington, Andrea M.
Vetter, Irina
Dekan, Zoltan
Muttenthale, Markus
Wan, JingJing
Lewis, Richard J.
King, Glenn F.
Brierley, Stuart M.
Alewood, Paul F.
Title Selenoether oxytocin analogues have analgesic properties in a mouse model of chronic abdominal pain
Journal name Nature Communications   Check publisher's open access policy
ISSN 2041-1723
Publication date 2014-01-01
Year available 2014
Sub-type Article (original research)
DOI 10.1038/ncomms4165
Open Access Status File (Publisher version)
Volume 5
Start page 3165.1
End page 3165.12
Total pages 12
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Subject 1600 Chemistry
1300 Biochemistry, Genetics and Molecular Biology
3100 Physics and Astronomy
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.
Keyword Multidisciplinary Sciences
Science & Technology - Other Topics
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 1063803
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
Institute for Molecular Bioscience - Publications
Centre for Advanced Imaging Publications
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Citation counts: TR Web of Science Citation Count  Cited 29 times in Thomson Reuters Web of Science Article | Citations
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Created: Wed, 19 Feb 2014, 03:58:11 EST by Sandrine Ducrot on behalf of Centre for Advanced Imaging