Structure-function and domain minimization of insulin-like peptide 3, a novel member of the insulin superfamily.

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Insulin-like peptide 3 (INSL3) is a peptide hormone that is structurally similar to insulin. It is produced in both the testes and the ovaries. In the male, one of its primary roles is to initiate testes descent during fetal development via a direct action on the gubernaculum ligament. Failure of INSL3 action either directly or due to receptor malfunction causes cryptorchidism (undescended testes), one of the most common congenital defects. In the female, INSL3 is implicated in follicle selection. More recent evidence shows that the peptide has clear roles in modulating male and female germ cell maturation. These effects indicate that agonists and antagonists of INSL3 have potential as specific drugs for novel contraceptive approaches or infertility treatments in both sexes. The actions of INSL3 are mediated by interaction with a G-protein coupled receptor known as LGR8. This receptor is expressed in the testes and ovary as well as several other tissues including the brain. However, very little is known about how INSL3 interacts with LGR8 to produce its physiological responses. Consequently, we will determine the structural features of the peptide that are responsible for receptor binding. This will be achieved by use of chemical peptide synthesis of not only INSL3 but also of analogues of the peptide that contain modified residues or domains. These will be assayed for characteristic INSL3 activity and the results, together with those acquired by modern biomolecular interaction analyses, will be used to identify the receptor binding regions for INSL3. This information, together with a determination of the three-dimensional structure of INSL3 by using NMR spectroscopy, will then be disseminated using computer-assisted molecular modelling to design smaller, more stable, orally active analogues. Such mimetics of reduced size that are correspondingly cheaper and simpler to prepare and handle will have great potential for therapeutic regulators of human fertility.