Quick Project Snapshot
Novel insulin mimetics for managing diabetes
INSL3 is highly expressed in the Leydig cells of the testis and has a critical role in testis descent. INSL3 knockout mice are cryptorchid and as a result infertile. INSL3 plays an important role in the development of the gubernaculum and also seems to have a role in the maintenance of fertility in females. The effects of INSL3 are mediated through the G protein-coupled receptor, RXFP2.
The SAR data suggest that part of both A and B-chain are necessary for RXFP2 agonistic activity. Consequently a minimized INSL3 was designed and synthesized, INSL3 A5–26/B7–27 that retained near native agonistic activity. This peptide contains truncated A- and B-chain and is almost one-quarter smaller than the native peptide and thus easier and cheaper to make and represents a potential lead peptide for further development as a fertility regulator.
As the B-chain contains the key residues for binding the LRR domain, INSL3 B-chain analogues have been designed and developed as functional antagonists.
The lack of structural support from the A-chain resulted in poor affinity of the B-chain specific antagonist. Thus a synthetic parallel dimer of INSL3 B-chain was developed that exhibited high RXFP2 affinity and antagonized INSL3-mediated cAMP signalling through RXFP2. Further refinement by truncation of 18 residues yielded a minimized analogue, INSL3:B10-24/B1-31 that retained full binding affinity and INSL3 antagonism. This is an attractive lead for in vivo evaluation as an inhibitor of male and female fertility. We will further develop the lead peptides (agonist and antagonist) for effective treatment of fertility disorders.
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.