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Novel insulin-like peptide 5 mimetics for controlling colon motility

Constipation is a serious problem that accounts for ~8 million annual physician visits (USA) and is associated with significant morbidity and reduced quality of life.

However, current treatments are generally ineffective which highlights the need for the development of alternative therapeutic strategies. My team, together with international collaborators from both academia and the pharmaceutical company, Takeda, has been investigating a novel gut hormone, insulinlike peptide 5 (INSL5), produced by colonic L-cells.

It acts through a G protein-coupled receptor, RXFP4 which is present in the enteric neurons. Our recent unpublished data suggest that INSL5 is an important regulator of colonic motility and has potential application for treating constipation.

Therefore, further studies are required to fully validate this system as a drug target. In a major advance, we recently chemically synthesised a minimised INSL5 analog which is significantly easier to assemble in large quantity compared with native INSL5.

In this project, we will further optimise this peptide to produce the smallest possible agonist with high RXFP4 affinity. As the minimisation of the structure causes loss of plasma stability, we will chemically modify the analog to improve its in vivo half-life to allow testing in animal models of constipation.

To fully understand INSL5 action in the colon, we will investigate the intracellular signaling pathways activated by both INSL5 and our novel RXFP4 agonists in colonic enteric neurons.

These results will be correlated with testing of both INSL5 and the novel agonist in clinically relevant animal models of colon motility.

Finally, our developed longer-acting INSL5 analogs will be tested in animal models of constipation. This work will provide new information about the function of INSL5 in the colon and confirm RXFP4 as a valid pharmaceutical target for treating constipation.

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