Amyloid deposits of human islet amyloid polypeptide (hIAPP, also known as amylin) play a key role in Type-2 diabetes (diabetes mellitus). Amyloid deposits composed of hIAPP can be found in approximately 95% of all Type-2 diabetes patients and have been associated with hyperglycemia and the loss of insulin producing ?-cells. While amyloid deposits often serve as markers of disease pathology, it is believed that the cytotoxic effect of amyloid fibrils is actually due to soluble oligomers. These soluble oligomers have been linked to cell membrane disruption and cell death. Inhibition of amylin self-assembly may be a potential therapeutic strategy for the treatment of Type-2 diabetes. Amylin is a 37-residue polypeptide that is co-secreted with insulin. Amyloid fibrils composed of hIAPP display an architecture known as the ?cross-? motif?. In this type of structure, repeating units of extended polypeptide chains, in the ?-sheet conformation, run perpendicular to the long axis of the amyloid fibril. Amylin has been found to associate with insulin. This association is believed to stabilize amylin and may prevent it's self-assembly. Based on the insulin-hIAPP interaction, it is the overall goal of this proposal to acquire peptoid- based helical mimetics of the 9-20 region of the insulin B-chain that may serve as potential inhibitors of amylin aggregation. Towards this end, peptoid helices will be synthesized and their ability to inhibit amyloid formation characterized through the use of kinetic aggregation assays, circular dichroism and vibrational spectroscopy as well as transmission electron microcopy. Inhibitors will be optimized through the construction and screening of spatially focused compound libraries. Lead compounds will be resynthesized on a larger scale and their effects on the amyloidogenic propensity of hIAPP thoroughly characterized.
Aggregation of human islet amyloid polypeptide (hIAPP) and the subsequent formation of amyloid deposits in the pancreas are pivotal to the onset of Type-2 diabetes. The main focuses of this proposal is the design, synthesis and characterization of compounds that may serve as potential inhibitors of hIAPP aggregation. Such compounds may provide a template for potential therapeutic intervention.
