Inhibitors of Amyloid Formation by Islet Amyloid Polypeptide
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Amyloid deposition is a characteristic component of many human diseases, including Alzheimer's disease, Parkinson's disease and type 2 diabetes. Human islet amyloid polypeptide (IAPP also known as amylin) is the major protein component of the pancreatic islet amyloid associated with type 2 diabetes. There is considerable interest in developing inhibitors of amyloid formation, both because of their obvious therapeutic potential but also because they can provide powerful tools for mechanistic studies. In this dissertation, peptide based inhibitors were rationally designed and a general strategy was developed whereby two moderate inhibitors of amyloid formation can be rationally selected via kinetic assays and combined to yield a highly effective inhibitor. Small molecule inhibitors were also developed. Rifampicin is reported to inhibit Aβ amyloid formation, but it does not prevent amyloid formation by IAPP, instead it interferes with standard fluorescence based assays of amyloid formation. Simple sulphonated triphenyl methane derivatives are potent inhibitors of in vitro amyloid formation by IAPP. The tea-derived flavanol, (-)-Epigallocatechin 3-Gallate, is an effective inhibitor of in vitro IAPP amyloid formation and disaggregates preformed amyloid fibrils derived from IAPP. IAPP is produced as a prohormone, proIAPP, and processed in the secretory granules of the pancreatic beta cells. Partially processed forms of proIAPP are found in amyloid deposits. It has been suggested that incomplete processing plays a role in amyloid formation by promoting interactions with sulfated proteoglycans of the extracellular matrix. Biophysical evidences are provided for the role of proIAPP processing intermediate and sulfated proteoglycans in amyloid formation. Simple sulfonated triphenyl methyl derivatives inhibit amyloid formation by proIAPP processing intermediate and also inhibit glycosaminoglycans mediated amyloid formation by proIAPP processing intermediate. These studies may give a better understanding of the mechanism of amyloid formation and provide valuable insight into the development of effective therapeutic strategies for a wide range of amyloidogenic diseases.