Interaction of Human Islet Amyloid Polypeptide with Model Membranes in the Presence of a Novel Oligomer Modulator “anle138B”

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 insulin producing beta-cells, their inhibition may be an effective strategy for the prevention and/ or treatment of the disease. Here, we present the results of lipid monolayer insertion, vesicle leakage and ThT aggregation assays of IAPP in the presence of anti-amyloid compounds. Among several tested inhibitors, “anle138b”, a novel modulator of oligomer formation [2] was particularly effective in inhibiting IAPP fibril formation and membrane disruption. Interestingly, the protective activity of anle138b was most significant even at low sub-stoichiometric proportions (1 to 10 molar ratio of anle138b to IAPP). We investigate the effect of anle138b on synthetic fragments of IAPP and model membranes to further dissect the molecular mechanism of the inhibition. Our findings so far suggest that anle138b is a potent amyloid blocker, that reduces membrane damage by effectively hindering IAPP aggregation and that has the potential to be a disease-modifying agent for type-2 diabetes.[1] Engel M et al., PNAS. (2008) - 105 :6033.[2] Wagner J et al., Acta Neuropathologica (2013) - 125: 795.Keywords: IAPP, membrane models, anle138b, amyloid inhibitor.