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

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dc.contributor.authorde Araujo, A.
dc.contributor.authorMobli, M.
dc.contributor.authorCastro, J.
dc.contributor.authorHarrington, A.
dc.contributor.authorVetter, I.
dc.contributor.authorDekan, Z.
dc.contributor.authorMuttenthaler, M.
dc.contributor.authorWan, J.
dc.contributor.authorLewis, R.
dc.contributor.authorKing, G.
dc.contributor.authorBrierley, S.
dc.contributor.authorAlewood, P.
dc.date.issued2014
dc.description.abstractPoor 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.
dc.description.statementofresponsibilityAline Dantas de Araujo, Mehdi Mobli, Joel Castro, Andrea M. Harrington, Irina Vetter, Zoltan Dekan, Markus Muttenthaler, w, JingJing Wan, Richard J. Lewis, Glenn F. King, Stuart M. Brierley, Paul F. Alewood
dc.identifier.citationNature Communications, 2014; 5(1):3165-1-3165-12
dc.identifier.doi10.1038/ncomms4165
dc.identifier.issn2041-1723
dc.identifier.issn2041-1723
dc.identifier.orcidCastro, J. [0000-0002-5781-2224]
dc.identifier.orcidHarrington, A. [0000-0002-1562-4137]
dc.identifier.orcidBrierley, S. [0000-0002-2527-2905]
dc.identifier.urihttp://hdl.handle.net/2440/94371
dc.language.isoen
dc.publisherNature
dc.rights© 2014 Macmillan Publishers Limited. All rights reserved.
dc.source.urihttps://doi.org/10.1038/ncomms4165
dc.subjectChemical sciences; medical research; medicinal chemistry
dc.titleSelenoether oxytocin analogues have analgesic properties in a mouse model of chronic abdominal pain
dc.typeJournal article
pubs.publication-statusPublished

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