Developing peptidomimetics of insulin-like peptide 5, a novel orexigenic gut hormone, to target its GPCR, RXFP4
Obesity has been termed a “worldwide epidemic” by the World Health Organisation (WHO). Conversely, anorexia and cachexia are significant health problems that cause high mortality.
Our collaborators and we have identified insulin-like peptide 5 (INSL5) as a novel orexigenic gut hormone which promotes appetite during conditions of energy deprivation. It is only the second orexigenic hormone to be discovered after ghrelin. Its G-protein coupled receptor, RXFP4, is thus a potentially very important therapeutic target for treating human conditions with reduced food intake, whereas an RXFP4 antagonist may be of therapeutic use for the treatment of obesity. In a significant achievement, we recently developed a simplified INSL5 analogue with potent agonist actions at RXFP4. This peptide, we named Analogue 5, has just two disulfide bonds (compared with three for INSL5) and is thus easier to assemble in large quantity to validate the target in animal models. We now propose to minimize and simplify this peptide further to produce a small "drug-like" structure having potent activity. To minimize the structure, we will sequentially truncate this peptide from the N-terminus of the B-chain. We will determine the activation domains by structure-activity relationship studies and then replace or truncate those domains in order to achieve an antagonist. In addition, we will aim to develop single chain RXFP4 agonist or antagonist by using stapling (click chemistry/dicarba technology). These novel peptides will undergo comprehensive pharmacological and structural characterisation in order to confirm their native peptide-like activity and structures. These minimized peptides will be attractive and very important pharmacological tools for studying the physiological role of the INSL5/RXFP4 system in preclinical animal models. In addition, they can be developed as candidate therapeutic entities: as agonists or antagonists of RXFP4 with potential uses in treating human conditions such as anorexia and obesity.
Brain health affects all Australians. You can support our research by making a donation or a bequest.