A Hot-Segment-Based Approach for the Design of Cross-Amyloid Interaction Surface Mimics as Inhibitors of Amyloid Self-Assembly
A Hot-Segment-Based Approach for the Design of Cross-Amyloid Interaction Surface Mimics as Inhibitors of Amyloid Self-Assembly
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DOI：
10.1002/anie.201504973
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发表时间：
2015-10-26
影响因子：
16.6
通讯作者：
Kapurniotu, Aphrodite
中科院分区：
文献类型：
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作者：
Andreetto, Erika;Malideli, Eleni;Kapurniotu, Aphrodite
设计蛋白质-蛋白质相互作用的抑制剂介导淀粉样蛋白自组装是一个重大的挑战，主要是由于所涉及的结构和界面的动态性质。淀粉样蛋白多肽与其他蛋白质的相互作用是自组装的重要调节剂。在这里，我们提出了一个热段连接的方法来设计一系列的模拟物的IAPP交联淀粉样蛋白的相互作用表面与A（ISMs）的淀粉样蛋白生成和细胞毒性的A，IAPP，或两种多肽的纳摩尔抑制剂。接头的性质决定了ISM结构和抑制功能，包括效力和靶标选择性。重要的是，ISM有效地抑制自接种和交叉接种的IAPP自组装。我们的研究结果提供了一类新型的高效肽先导物，用于靶向阿尔茨海默病、2型糖尿病或这两种疾病中的蛋白质聚集，以及抑制淀粉样蛋白自组装和其他蛋白质的致病相互作用的化学方法。
The design of inhibitors of protein-protein interactions mediating amyloid self-assembly is a major challenge mainly due to the dynamic nature of the involved structures and interfaces. Interactions of amyloidogenic polypeptides with other proteins are important modulators of self-assembly. Here we present a hot-segment-linking approach to design a series of mimics of the IAPP cross-amyloid interaction surface with A (ISMs) as nanomolar inhibitors of amyloidogenesis and cytotoxicity of A, IAPP, or both polypeptides. The nature of the linker determines ISM structure and inhibitory function including both potency and target selectivity. Importantly, ISMs effectively suppress both self- and cross-seeded IAPP self-assembly. Our results provide a novel class of highly potent peptide leads for targeting protein aggregation in Alzheimer's disease, type 2 diabetes, or both diseases and a chemical approach to inhibit amyloid self-assembly and pathogenic interactions of other proteins as well.