Inhibition of IAPP Toxicity and Aggregation into β– Sheets and Amyloid by a Rationally N-Methylated, IAPP Amyloid Core-Containing Hexapeptide

Pancreatic amyloid is present in more than 95% of type II diabetes patients and is formed by the aggregation of the 37-residue polypeptide islet amyloid polypeptide (IAPP). Insoluble IAPP amyloid aggregates colocalize with areas of cellular degeneration and have been, therefore, linked to the progressive deterioration of β-cell function and the pathogenesis of type II diabetes. IAPP amyloid forms via a conformational transition of soluble, mainly disordered IAPP into aggregated β-sheets. NF(N-Me)GA(N-Me)IL is a rationally N-methylated, IAPP amyloid core-containing synthetic hexapeptide that was designed based on a recently developed amyloid inhibitor design strategy. The strategy aims at converting amyloidogenic sequences into non-amyloidogenic ones via conformational restriction that is achieved by selective N-methylation of a minimum number of amide bonds on the same side of the strand of the β-sheet of the amyloid core region.