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 journalArticle

    70 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)Art: 3165
    Number of pages12
    JournalNature Communications
    Volume5
    DOIs
    Publication statusPublished - 2014

    Fingerprint Dive into the research topics of 'Selenoether oxytocin analogues have analgesic properties in a mouse model of chronic abdominal pain'. Together they form a unique fingerprint.

    Cite this