TY - JOUR
T1 - Selenoether oxytocin analogues have analgesic properties in a mouse model of chronic abdominal pain
AU - de Araujo, Aline
AU - Mobli, Mehdi
AU - Castro Kraftchenko, Joel
AU - Harrington, Andrea
AU - Vetter, Irina
AU - Dekan, Zoltan
AU - Muttenthaler, Markus
AU - Wan, Jingjing
AU - Lewis, Richard
AU - King, Glenn
AU - Brierley, Stuart
AU - Alewood, Paul
PY - 2014/1/30
Y1 - 2014/1/30
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84897974548&partnerID=8YFLogxK
U2 - 10.1038/ncomms4165
DO - 10.1038/ncomms4165
M3 - Article
VL - 5
SP - Art: 3165
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 3165
ER -