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Islet amyloid polypeptide (IAPP, amylin) is responsible for amyloid formation in type 2 diabetes and in transplanted islets. The flavanol (-)-epigallocatechin-3-gallate [EGCG; (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl 3,4,5-trihydroxybenzoate] is an effective inhibitor of amyloid formation by IAPP; however, the interactions required for the inhibition of IAPP amyloid formation and for the remodeling of amyloid fibers are not known. A range of features have been proposed to be critical for EGCG protein interactions, including interactions with aromatic residues, interactions with amino groups, or sulfhydryls. Using a set of IAPP analogues, we show that none of these are required. Studies in which EGCG is added to the lag phase of amyloid formation shows that it interacts with intermediates as well as with monomers and amyloid. The features of EGCG required for effective inhibition were examined. The stereoisomer of EGCG, (-)-gallocatechin gallate (GCG), is an effective inhibitor, although less so than EGCG. Removing the gallate ester moiety leads to EGC which is a less effective inhibitor. Removing only the 3-hydroxyl group of the trihydroxyphenyl ring leads to a compound that has more pronounced effects on the lag phase than EGC but is less effective at reducing the amount of amyloid. Elimination of both the 3-hydroxy group and the gallate ester results in loss of activity. EGCG remodels IAPP amyloid fibers but does not fully resolubilize them to unstructured monomers, and the remodeling is not the reverse of amyloid assembly. The ability of the compounds to remodel IAPP amyloid closely follows their relative ability to inhibit amyloid formation.

Analysis of the Inhibition and Remodeling of Islet Amyloid Polypeptide Amyloid Fibers by Flavanols