IGFBP 3 LIGAND INHIBITORS FOR THE TREATMENT OF DIABETES

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DESCRIPTION (Adapted from applicant's abstract): Insulin-like growth factor-I (IGFI) is an important anabolic peptide which mimics many of the actions of insulin and growth hormone. IGFI has insulin-like metabolic and trophic effects and promotes the expression of many differentiated functions. The majority of IGFI circulates in blood as a biologically inactive trimolecular complex of 150 kDa consisting of IGF-binding protein-3 (IGFBP-3), an acid labile subunit (ALS) and IGFI. Ligands or drugs which inhibit the interaction of IGFI with IGFBP-3 should increase biologically active levels of free IGFI in plasma and have utility for the treatment of insulin and non-insulin dependent diabetes. Here the investigators propose to (1) Determine the effects of a selective peptide IGFBP-3 ligand inhibitor, [L24, 59, 60, A31] hIGFI, which does not interact with IGF or insulin receptors, on blood glucose levels in animal models of diabetes and (2) Validate a high throughput screening assay for human IGFBP-3 and screen an in-house chemical library of about 45,000 organic molecules in order to identify a non-peptide lead. The second phase of the proposal will optimize the non-peptide small molecule leads using a directed chemistry approach for the development of orally active drugs for the treatment of insulin and non-insulin dependent diabetes.