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

Aline de Araujo, Mehdi Mobli, Joel Castro Kraftchenko, Andrea Harrington, Irina Vetter, Zoltan Dekan, Markus Muttenthaler, Jingjing Wan, Richard Lewis, Glenn King, Stuart Brierley, Paul Alewood

    Research output: Contribution to journalArticlepeer-review

    77 Citations (Scopus)


    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.

    Original languageEnglish
    Article number3165
    Pages (from-to)Art: 3165
    Number of pages12
    JournalNature Communications
    Publication statusPublished - 30 Jan 2014


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