SYNTHESIS OF INSULIN MEDIATOR AND RELATED STRUCTURES

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Recent studies have shown that insulin stimulates the release of a soluble mediator(s) from the plasma membrane which produces insulin-like activities in several biochemical assays. Results from enymatic treatment and composition analysis indicated that its structure may be analogous to a unique type of glycosyl phosphatidylinositol complex, which is commonly involved in the anchoring of many membrane proteins. To substantiate this structural hypothesis and especially to define the stereochemistry of postulated partial structures, we propose to synthesize several oligosaccharide and glycolipid derivatives for comparative studies. These inlcude 2-amino-2-deoxy-D-glucopyroanosyl-(alpha or beta) - (1, 4 or 1, 3 or 1, 5)-myo-inositol-1-phosphate (1), 6-0- (2-aminoethoxyphosphoryl)-D-mannose (2), phospholipid derivatives of 1, and conjugates of 1 and 2 as simplified models of the glycosyl inositol complex. Pending the current analysis of a peptide component in the insulin mediator, the corresponding peptide derivatives will also be synthesized. These compounds will be compared with degradation products of the insulin mediator in spectroscopic and chromatographic systems. They will also be evaluated in 4 enzyme assays and one intact cell assay as full or partial agonists or antagonists of the insulin mediator. After the correct partial structures of the mediator are identified, they will be coupled to carrier proteins for the generation of monoclonal antibodies. These antibodies will be used to facilitate the mechanistic studies of the insulin mediator and the mapping of membrane proteins anchored by glycosyl phosphatidylinositol. The structural information will also provide a rational basis for the design and synthesis of photoactive irreversible inhibitors of the insulin mediator as biochemical probes and orally active insulin-mimics as novel anti-diabetic agents.