Membrane-catalysed misfolding of islet amyloid polypeptide is associated with the death of β-cells in type II diabetes (T2D). Most active compounds so far reported require high doses for inhibition of membrane bound IAPP fibrillation. Here, we describe a naphthalimide-appended oligopyridylamide-based α-helical mimetic, DM 1, for targeting membrane bound IAPP. DM 1 completely inhibits the aggregation of IAPP at doses of 0.2 equivalents. DM 1 is also effective at similarly low doses for inhibition of seed-catalyzed secondary nucleation. An NMR based study demonstrates that DM 1 modulates IAPP self-assembly by stabilizing and/or perturbing the N-terminus helix conformation. DM 1 at substoichiometric doses rescues rat insulinoma cells from IAPP-mediated cytotoxicity. Most importantly, 0.2 equivalents of DM 1 disaggregate preformed oligomers and fibrils and can reverse cytotoxicity by modulating toxic preformed oligomers and fibrils of IAPP into non-toxic conformations.

中文翻译：

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IAPP 聚集的亚化学计量抑制：抗淀粉样蛋白药物的拟肽方法

胰岛淀粉样多肽的膜催化错误折叠与 II 型糖尿病 (T2D) 中 β 细胞的死亡有关。迄今为止报道的大多数活性化合物需要高剂量来抑制膜结合 IAPP 纤维化。在这里，我们描述了一种附加萘二甲酰亚胺的基于低聚吡啶基酰胺的 α-螺旋模拟物，DM 1，用于靶向膜结合 IAPP。DM 1以 0.2 当量的剂量完全抑制 IAPP 的聚集。DM 1在同样低的剂量下也能有效抑制种子催化的二次成核。一项基于 NMR 的研究表明，DM 1通过稳定和/或扰乱 N 端螺旋构象来调节 IAPP 自组装。DM 1以亚化学计量剂量拯救大鼠胰岛素瘤细胞免受 IAPP 介导的细胞毒性。最重要的是，0.2 当量的DM 1 可以分解预先形成的寡聚体和原纤维，并且可以通过将 IAPP 的有毒预先形成的寡聚体和原纤维调节成无毒构象来逆转细胞毒性。