Oxytocin mimetics

Poor oral availability and susceptibility to reduction and protease degradation is a major hurdle in peptide drug development for peripheral or central nervous system candidates. In contrast, druggable 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 have developed novel chemoselective strategies to engineer non-reducible stable oxytocin analogues that are equipotent to native oxytocin. Moreover, we describe single atom modifications to oxytocin disulfide bridges produce ligands with improved selectivity across species. Nuclear magnetic resonance structural analysis of native oxytocin and the seleno-oxytocin derivatives reveals that oxytocin has a pre-organized turn structure in solution, in marked contrast to earlier X-ray crystallography studies. These seleno-oxytocin analogues potently inhibit colonic nociceptors both <i>in vitro</i> and <i>in vivo</i> in mice with chronic visceral hypersensitivity. Our findings have important implications for the clinical use of oxytocin analogues and disulfide-rich peptides in general