Quick Project Snapshot
Novel relaxin-3 mimetics for controlling feeding and motivated behaviour
Eating disorders and addictions, in particular obesity and excessive food consumption, are a major health concern in Australia and worldwide; and there is an urgent need to better and fully define the neurochemicals and neural circuits controlling motivated appetitive and consummatory behaviours.
Relaxin-3 (R3) is a highly conserved neuropeptide transmitter that can regulate a number of important physiological processes including arousal-, stress- and reward-related circuits and resultant behaviours, including feeding.
Central administration of R3 or agonist analogues increases feeding, while antagonizing R3 signalling inhibits consumption of highly-palatable food and other appetitive drives.
These findings suggest that the R3 receptor, RXFP3, is a potential target for pharmacological control of eating and addictive disorders.
The characterization of the physiological functions of R3/RXFP3 signalling has, however, been hampered by a lack of selective and readily available ligands for RXFP3.
Exogenous native R3 has poor selectivity for RXFP3 and its complex two-chain peptide structure renders it difficult and expensive to produce chemically. In a major breakthrough, our team together with our collaborator Dr Johan Rosengren overcome these limitations by developing potent minimized peptide agonists and antagonists for RXFP3, the first single-chain relaxin peptide analogues with nanomolar affinity.
The objectives of this proposal are to use innovative medicinal chemistry approaches to further develop/modify these linear peptides to optimize BBB penetration and in vivo stability; and to use these peptides to study the role of the R3/RXFP3 system in modulating neuronal signalling and behaviour in order to validate it as a drug target.
These novel peptides are patented and they represent new leads for future development and preclinical testing.
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.