SUN-252 Rescue of Function of Inactivating Mutations in Human GPCRs in the Reproductive Hypothalamic-Pituitary-Gonadal Axis

Inactivating mutations have been described for human GPCRs at all levels of the reproductive hypothalamic-pituitary-gonadal (HPG) axis which results in reproductive incompetence. The majority of the mutations in GPCRs give rise to misfolding and a failure to traffick to the cell surface. We have interrogated data bases for cell-permeant small molecules which bind to and stabilise the GPCR as it emerges from the endoplasmic reticulum and hence facilitate trafficking of the mutant GPCR to the cell membrane and restoration of function. In this way we have successfully ‘rescued’ function of mutant Neurokinin B, GnRH, LH and FSH receptors using small molecule antagonists which bind orthosterically or agonists which bind allosterically. These discoveries represent an advance towards novel personalized medicine for GPCR deficiencies in the human HPG axis.