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Development of Peptide-Based Inhibitors of Amylin Aggregation Employing Aromatic and Electrostatic Repulsion

  • Adam A. Profit
  • Ruel Z. B. Desamero
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1824)

Abstract

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 words

Amylin, amyloid, type 2 diabetes Raman Peptide Thioflavin-T assays 

Notes

Acknowledgments

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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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of ChemistryYork College and The Institute for Macromolecular AssembliesJamaicaUSA
  2. 2.Ph.D. Programs in Chemistry and BiochemistryThe Graduate Center of the City University of New YorkNew YorkUSA

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