Quick Project Snapshot
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 Our recent unpublished data suggest that INSL5 is an important regulator of colonic motility and has potential application for treating constipation.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.
Insulin Peptides Group
Insulin is one of the most clinically important peptide drugs on the market. It still represents the only treatment for diabetes (particularly for type 1). There are seven other insulin-like peptides (also called the relaxin family of peptides: H1, H2 and H3 relaxins, INSL3, 4, 5 and 6) which have similar structures to insulin (2 chains, 3 disulfide bonds), but have a diverse range of physiological functions. H2 relaxin is the most studied peptide in our laboratory and has recently passed phase III clinical trials for the treatment of acute heart failure. Our interest and experience lies in the design and development of insulin and insulin-like peptide-based drugs.
All Projects by this LabDeveloping peptidomimetics of insulin-like peptide 5, a novel orexigenic gut hormone, to target its GPCR, RXFP4Developing novel chemical methods to produce insulin mimeticsDeveloping small peptidomimetics to target RXFP1 for the treatment of acute heart failureNovel single-chain peptide mimetics, B7-33, for the treatment of fibrosisNovel relaxin-3 mimetics for controlling feeding and motivated behaviourNovel insulin-like peptide 5 mimetics for controlling colon motilityNovel insulin mimetics for managing diabetes
The Neuropeptides Division primarily conducts multi-disciplinary studies on the relaxin family of peptides/hormones and their receptors. The division focuses on determining the role of these peptides and the receptors they target a wide range of physiological and disease states. These studies are coupled with fundamental drug discovery research on both these and other peptides and their G protein-coupled receptors. The aim of this research is to develop new biological knowledge and fundamental understanding about how to best therapeutically target these peptide systems with the long term view to develop drugs which target the peptide receptors to treat vascular, fibrotic, metabolic and psychiatric diseases.
An example of the success of this approach is the completion of a Phase III trial using the hormone relaxin for the treatment of acute heart failure by the Swiss Pharmaceutical Company Novartis. A Phase IIIb trial is ongoing and the relaxin drug, serelaxin, has been approved in Russia to treat patients with acute heart failure. Hence fundamental research on the mechanism of action of a hormone, in the case of relaxin pioneered at the Florey by the former Neuropeptides Division Head, Prof Geoffrey Tregear, can ultimately lead to its use to treat disease in patients.