The Novel Inhibitor “Anle145C” Efficiently Inhibits Fibril Formation of Islet Amyloid Polypeptide (IAPP) and uses Distinctly Different Modes of Action in the Absence and Presence of Membranes

Abstract

Amyloid formation in the pancreas by islet amyloid polypeptide (IAPP) is closely associated with type-2 diabetes. Compelling evidence indicates that membranes play a crucial role in contributing to IAPP amyloid formation and that IAPP amyloid formation leads to cell membrane disruption [1]. Since both IAPP amyloid formation and membrane damage are considered perilous to the pancreatic beta-cells, their inhibition may be an effective strategy for the prevention and/ or treatment of the disease. Here, we studied the interaction between a novel amyloid inhibitor “anle145c” [2] and IAPP in the absence and presence of model membranes. Our results suggest that addition of anle145c to IAPP inhibits IAPP fibril growth even at sub-stoichiometric concentrations, both in the absence and presence of membranes. Anle145c also reduces membrane damage induced by IAPP but does not induce membrane leakage by itself. Most notably, anle145c shows a strong membrane interaction, resulting in a distinctly different mode of inhibition than in the absence of membranes. We present a model in which anle145c interacts with oligomeric IAPP species in solution, but with monomeric or early oligomeric IAPP species in the presence of membranes.[1] Engel M et al., PNAS. (2008) - 105 :6033[2] Wagner J et al., Acta Neuropathologica (2013) - 125: 795