Oxytocin analogues for the oral treatment of abdominal pain

Abdominal pain presents an onerous reality for millions of people affected by gastrointestinal disorders such as irritable bowel syndrome (IBS) and inflammatory bowel diseases (IBD). The oxytocin receptor (OTR) has emerged as a new analgesic drug target with OTR expression upregulated on colon-innervating nociceptors in chronic visceral hypersensitivity states, accessible via luminal delivery. However, the low gastrointestinal stability of OTR's endogenous peptide ligand oxytocin (OT) is a bottleneck for therapeutic development. Here, we report the development of potent and fully gut-stable OT analogues, laying the foundation for a new area of oral gut-specific peptide therapeutics. Ligand optimisation guided by structure-gut-stability-activity relationships yielded highly stable analogues (t_1/2>24 h, compared to t_1/2<10 min of OT in intestinal fluid) equipotent to OT (~3 nM) and with enhanced OTR selectivity. Intra-colonic administration of the lead ligand significantly reduced colonic mechanical hypersensitivity in a concentration-dependent manner in a mouse model of chronic abdominal pain. Moreover, oral administration of the lead ligand also displayed significant analgesia in this abdominal pain mouse model. The generated ligands and employed strategies could pave the way to a new class of oral gut-specific peptides to study and combat chronic gastrointestinal disorders, an area with substantial unmet medical needs.