Small Molecule Modulators of Amyloid Formation by Islet Amyloid Polypeptide

Abstract

Amyloid formation is involved in many human diseases. Examples include Alzheimer's, Huntington's, and Parkinson's disease, and type-2 diabetes. Islet Amyloid Polypeptide (IAPP) is a protein that is co-secreted with insulin in pancreatic beta-cells; however, IAPP is an extremely amyloidogenic protein. There is a considerable amount of interest to develop inhibitors for amyloid formation. A large body of work has been focused on the development of inhibitors for the A-beta peptide of Alzheimer's disease, but fewer inhibitors have been developed for IAPP. In this thesis, small molecules were developed to alter fiber formation kinetics. This thesis described studies of the ability of Morin Hydrate to inhibit and S-Flurbiprofen to accelerate IAPP amyloid formation. Both of these compounds have been analyzed and proposed to be inhibitors of A, but they have not been tested on IAPP. Morin hydrate, a hydroxyflavone, can be found in fruits of plants and S-flurbiprofen is a non-steroidal anti-inflammatory drug (NSAID) that is a derivative of naturally occurring molecules found in plants. It is thought that the toxic intermediates that these amyloidgenic peptides form are the central cause of these amyloidgenic diseases; not necessarily the fibers. These studies demonstrate two different approaches to inhibit amyloid toxicity. One method is to inhibit amyloid formation directly and avoid producing the toxic intermediates. The other method is to accelerate the kinetics at assembly past the toxic oligomeric state straight into fibers. These studies may give a better understanding of the mechanism of amyloid formation and possibly assist in developing effective therapeutic strategies for different amyloidgenic diseases.