Selenoether oxytocin analogues have analgesic properties in a mouse model of chronic abdominal pain.
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.
Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
Aline Dantas
AD
de Araujo
1] Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia [2] Centre for Advanced Imaging, The University of Queensland, St Lucia, Queensland 4072, Australia.
Mehdi
M
Mobli
1] Nerve-Gut Research Laboratory, Discipline of Medicine, The University of Adelaide, Adelaide, South Australia 5000, Australia [2] Department of Gastroenterology & Hepatology, Hanson Institute, Royal Adelaide Hospital, Adelaide, South Australia 5000, Australia.
Joel
J
Castro
1] Nerve-Gut Research Laboratory, Discipline of Medicine, The University of Adelaide, Adelaide, South Australia 5000, Australia [2] Department of Gastroenterology & Hepatology, Hanson Institute, Royal Adelaide Hospital, Adelaide, South Australia 5000, Australia.
Andrea M
AM
Harrington
Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
Irina
I
Vetter
Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
Zoltan
Z
Dekan
1] Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia [2].
Markus
M
Muttenthaler
Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
JingJing
J
Wan
Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
Richard J
RJ
Lewis
Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
Glenn F
GF
King
1] Nerve-Gut Research Laboratory, Discipline of Medicine, The University of Adelaide, Adelaide, South Australia 5000, Australia [2] Department of Gastroenterology & Hepatology, Hanson Institute, Royal Adelaide Hospital, Adelaide, South Australia 5000, Australia [3] Discipline of Physiology, Faculty of Health Sciences, The University of Adelaide, Adelaide, South Australia 5000, Australia.
Stuart M
SM
Brierley
Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
Paul F
PF
Alewood
D015746:Abdominal Pain / Q000188:drug therapy*; D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002908:Chronic Disease; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D010121:Oxytocin / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use
D000700:Analgesics; D010121:Oxytocin