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 minimised INSL3 was designed and synthesised, 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 antagonised INSL3-mediated cAMP signalling through RXFP2. Further refinement by truncation of 18 residues yielded a minimised analogue, INSL3:B10-24/B1-31 that retained full binding affinity and INSL3 antagonism. This is an attractive lead for in vivoevaluation as an inhibitor of male and female fertility. We will further develop the lead peptides (agonist and antagonist) for effective treatment of fertility disorders.

This project involves the development of new methods to produce insulin and novel insulin mimetics for the treatment of diabetes.