SAT-LB072 Pharmacological Chaperone Rescue of Function in Human HPG Axis GPCRs with Inactivating Mutations

Abstract

Inactivating mutations in G-protein coupled receptors (GPCRs) at all levels of the HPG axis give rise to incomplete reproductive development and adult infertility. The majority of the mutations in GPCRs cause misfolding of the receptor and a failure to traffic to the cell surface. We have identified cell permeant small molecule agonists and antagonists which can bind orthosterically or allosterically to stabilize the nascent GPCR in the endoplasmic reticulum and chaperone the mutant GPCR to the cell membrane. We have successfully 'rescued' many GnRH mutant receptors using small molecule antagonists which bind orthosterically. After removal of the antagonists the mutant GnRH receptors demonstrate good cell surface expression. Michael Conn's laboratory has demonstrated that such receptor rescue can restore reproductive competence in mice harboring an inactivating GnRH receptor mutation. We have also demonstrated rescue of cell surface expression and signaling in a substantial number of LH receptor mutations causing infertility in humans using a cell permeant allosteric agonist. This molecule is also able to rescue function in LHR binding and signalling deficient human mutations. Similarly we have rescued cell surface expression and signalling in human neurokinin B receptor mutations with an NKB antagonist and are exploring rescue of GPR54 utilising cell penetrating peptides. These discoveries represent an advance towards personalized medicine for GPCR deficiencies in the human HPG axis. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.