Quick Project Snapshot
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.
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.