Title |
Selenoether oxytocin analogues have analgesic properties in a mouse model of chronic abdominal pain
|
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Published in |
Nature Communications, January 2014
|
DOI | 10.1038/ncomms4165 |
Pubmed ID | |
Authors |
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, Paul F. Alewood |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United Kingdom | 3 | 43% |
Australia | 2 | 29% |
Japan | 1 | 14% |
Unknown | 1 | 14% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 7 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Spain | 1 | 1% |
France | 1 | 1% |
Unknown | 83 | 98% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 24 | 28% |
Researcher | 9 | 11% |
Student > Master | 8 | 9% |
Student > Bachelor | 5 | 6% |
Professor | 3 | 4% |
Other | 7 | 8% |
Unknown | 29 | 34% |
Readers by discipline | Count | As % |
---|---|---|
Chemistry | 25 | 29% |
Biochemistry, Genetics and Molecular Biology | 6 | 7% |
Pharmacology, Toxicology and Pharmaceutical Science | 5 | 6% |
Medicine and Dentistry | 5 | 6% |
Agricultural and Biological Sciences | 4 | 5% |
Other | 9 | 11% |
Unknown | 31 | 36% |