Islet amyloid polypeptide (IAPP) is a hormonal peptide, co-secreted with insulin in the pancreatic β-cells. IAPP samples a variety of conformations, starting from a native random coil to membrane-associated α-helical intermediates and eventually terminates in the amyloid plaques rich in β-sheet structures. A growing body of evidence suggests that membrane bound α-helical intermediates are the key cytotoxic species that impair the functionality and viability of β-cells and contribute to the onset of type 2 diabetes mellitus (DM2). An oligopyridylamide based helix mimetic DM 1, was found to be most effective antagonist of IAPP fibrillation in a physiologically relevant lipid membrane system. It induces/stabilizes a secondary structure in IAPP at substoichiometric concentration which potentially affects its downstream functions. DM 1 inhibits the primary and secondary nucleation process potentially binding to the monomer and small fiber states of IAPP. DM 1 also rescue IAPP-induced toxicity in cell culture. In this presentation, the design of the helical mimic and its application as inhibitor of IAPP aggregation using different techniques will be discussed.

Synthetic α-helical peptidomimetic for substoichiometric modulation of membrane bound IAPP aggregation

2019 Fall National Meeting

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