Development of Peptide-Based Inhibitors of Amylin Aggregation Employing Aromatic and Electrostatic Repulsion
Human islet amyloid polypeptide (hIAPP) is a 37-residue hormone that is co-stored and co-secreted with insulin. In type 2 diabetes, the polypeptide misfolds to form amyloid plaques in the pancreas. The self-assembly of hIAPP has been linked to the loss of insulin production and β-cell death. Recent investigations have revealed that soluble oligomers of hIAPP are the cytotoxic species responsible for β-cell death and not insoluble amyloid fibrils. Compounds that prevent the self-assembly of hIAPP or drive self-assembly to the state of innocuous insoluble amyloid may be of potential therapeutic value. In this report we summarize key methods employed in our efforts to identify peptide-based modulators of amylin self-assembly that utilize π-electronic effects or electrostatic charge repulsion. These peptide-based modulators may serve as lead compounds for the development of more drug-like molecules and demonstrate that tuning π-electron density and employing charged amyloid disrupting elements are viable approaches toward the design of potential amyloid inhibitors.
Key wordsAmylin, amyloid, type 2 diabetes Raman Peptide Thioflavin-T assays
The work presented here was supported in part by the Institute of General Medicine of the National Institutes of Health, grant # 5SC3GM89624 (to RZBD) and 1R15GM119040 (to RZBD and AAP).
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