Design of a mimic of nonamyloidogenic and bioactive human islet amyloid polypeptide (IAPP) as nanomolar affinity inhibitor of IAPP cytotoxic fibrillogenesis
Design of a mimic of nonamyloidogenic and bioactive human islet amyloid polypeptide (IAPP) as nanomolar affinity inhibitor of IAPP cytotoxic fibrillogenesis
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DOI：
10.1073/pnas.0507471103
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发表时间：
2006-02-14
影响因子：
11.1
通讯作者：
Kapurniotu, A
中科院分区：
文献类型：
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作者：
Yan, LM;Tatarek-Nossol, M;Kapurniotu, A
蛋白质在体内聚集成细胞毒性低聚体和纤维，与细胞退化和无法治愈的疾病的发病机制有关，而几种生物活性多肽和蛋白质在体外的高聚集倾向和不溶性阻碍了它们的治疗应用。人胰岛淀粉样多肽(IAPP)聚集到胰腺淀粉样蛋白与11型糖尿病的发病密切相关。IAPP是一种37个残基的多肽，是葡萄糖稳态的神经内分泌调节因子。然而，即使在纳摩尔浓度下，IAPP也会错误折叠并自结合成细胞毒性聚集体和纤维。由于IAPP聚集导致β细胞死亡，并阻止IAPP在糖尿病中的治疗应用，我们采用了一种微型化学设计方法来产生一种分子模拟的非淀粉样蛋白和生物活性的IAPP构象，该构象仍然能够与IAPP结合，从而抑制其纤维形成和细胞毒性。我们证明了双N-甲基化全长IAPP类似物[(N-Me)G24，(N-Me)126]-IAPP(IAPP-GI)是一种高度溶解的、无淀粉样变性、无细胞毒性的IAPP分子模拟物和APP受体激动剂。此外，IAPP-GI以低纳摩尔亲和力结合IAPP，并在低纳摩尔浓度范围内完全阻断IAPP的细胞毒自组装和纤维形成。重要的是，IAPP-GI可以解离细胞毒性IAPP寡聚体和纤维，并能够逆转它们的细胞毒性。双功能的可溶性IAPP模拟物结合了生物活性和阻断和逆转IAPP细胞毒自组装的能力，是治疗糖尿病的有前途的候选药物。此外，我们的淀粉样蛋白疾病抑制剂的设计理念可能适用于其他蛋白质聚集性疾病。
Protein aggregation into cytotoxic oligomers and fibrils in vivo is linked to cell degeneration and the pathogenesis of > 25 uncurable diseases, whereas the high aggregation propensity and insolubility of several bioactive polypeptides and proteins in vitro prevent their therapeutic use. Aggregation of human islet amyloid polypeptide (IAPP) into pancreatic amyloid is strongly associated with the pathogenesis of type 11 diabetes. IAPP is a 37-residue polypeptide that acts as a neuroendocrine regulator of glucose homeostasis. However, IAPP misfolds and self-associates into cytotoxic aggregates and fibrils even at nanomolar concentrations. Because IAPP aggregation causes beta-cell death and prohibits therapeutic application of IAPP in diabetes, we pursued a mininnalistic chemical design approach to generate a molecular mimic of a nonamyloidogenic and bioactive IAPP conformation that would still be able to associate with IAPP and thus inhibit its fibrillogenesis and cytotoxicity. We show that the double N-methylated full length IAPP analog [(N-Me)G24, (N-Me)126]-IAPP (IAPP-GI) is a highly soluble, nonamyloidogenic, and noncytotoxic IAPP molecular mimic and an APP receptor agonist. Moreover, IAPP-GI binds IAPP with low nanomolar affinity and completely blocks IAPP cytotoxic self-assembly and fibrillogenesis with activity in the low nanomolar concentration range. Importantly, IAPP-GI dissociates cytotoxic IAPP oligomers and fibrils and is able to reverse their cytotoxicity. Bifunctional soluble IAPP mimics that combine bioactivity with the ability to block and reverse IAPP cytotoxic self-assembly are promising candidates for the treatment of diabetes. Moreover, our amyloid disease inhibitor design concept may be applicable to other protein aggregation diseases.