Poster Presentation 14th Australian Peptide Conference 2022

Design and development of INSL5 analogues for the treatment of colon motility disorders (#246)

Hongkang Wu 1 , Ruslan Pustovit 1 2 , Xiaozhou Zhang 1 , Jamie Jie Mei Liew 1 , Mengjie (Oscar) Liu 1 , Ada Koo 1 , Lalita Oparija-Rogenmozere 1 , Qinghao Ou 1 , Martina Kocan 1 , Shuai Nie 3 , Ross Bathgate 1 4 , John Furness 1 2 , M. Akhter Hossain 1 5
  1. The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, MELBOURNE, Victoria, Australia
  2. Department of Anatomy and Physiology, The University of Melbourne, MELBOURNE, Victoria, Australia
  3. Melbourne Mass Spectrometry and Proteomics Facility, Bio21 Institute, The University of Melbourne, MELBOURNE, Victoria, Australia
  4. Department of Biochemistry and Pharmacology, The University of Melbourne, MELBOURNE, Victoria, Australia
  5. School of Chemistry, The University of Melbourne, MELBOURNE, Victoria, Australia

Insulin-like peptide 5 (INSL5) is a gut hormone that is exclusively produced by colonic L-cells. We have recently developed analogues of INSL5 that act as agonists for the relaxin family peptide receptor 4 (RXFP4) both in vitro and in vivo. We showed that INSL5-A13, an RXFP4 agonist, stimulates colorectal propulsion in wild-type mice, but not in RXFP4 knockout mice. These results suggest that INSL5 may have a physiological role in the control of colorectal motility. To investigate this possibility, we have recently designed and developed a novel INSL5 analogue, INSL5-A13NR. This compound is a potent antagonist in two in vitro assays and blocks agonist-induced increase in colon motility in mice that express RXFP4. Our data also show that colorectal propulsion induced by intracolonic administration of bacterial products (short-chain fatty acids, SCFAs) is antagonized by INSL5-A13NR. Our studies, therefore, suggest that RXFP4 is a potential drug target for the treatment of colon motility disorders such as constipation and diarrhea.