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.
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