Development of Peptide-Based Inhibitors of Amylin Aggregation Employing Aromatic and Electrostatic Repulsion.
Development of Peptide-Based Inhibitors of Amylin Aggregation Employing Aromatic and Electrostatic Repulsion.
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DOI：
10.1007/978-1-4939-8630-9_2
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发表时间：
2018
影响因子：
--
通讯作者：
A. Profit;R. Desamero
中科院分区：
文献类型：
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作者：
A. Profit;R. Desamero
人胰岛淀粉样多肽（hIAPP）是一种与胰岛素共储存和共分泌的37个残基的激素。在2型糖尿病中，多肽错误折叠以在胰腺中形成淀粉样斑块。hIAPP的自组装与胰岛素产生的损失和β细胞死亡有关。最近的研究表明，hIAPP的可溶性寡聚体是导致β细胞死亡的细胞毒性物质，而不是不溶性淀粉样蛋白原纤维。阻止hIAPP自组装或驱动自组装至无害的不溶性淀粉样蛋白状态的化合物可能具有潜在的治疗价值。在本报告中，我们总结了在识别利用π电子效应或静电电荷排斥的胰淀素自组装的基于肽的调节剂时采用的关键方法。这些基于肽的调节剂可以作为开发更多药物样分子的先导化合物，并证明调节π电子密度和采用带电淀粉样蛋白破坏元件是设计潜在淀粉样蛋白抑制剂的可行方法。
Human islet amyloid polypeptide (hIAPP) is a 37-residue hormone that is co-stored and co-secreted with insulin. In type 2 diabetes, the polypeptide misfolds to form amyloid plaques in the pancreas. The self-assembly of hIAPP has been linked to the loss of insulin production and β-cell death. Recent investigations have revealed that soluble oligomers of hIAPP are the cytotoxic species responsible for β-cell death and not insoluble amyloid fibrils. Compounds that prevent the self-assembly of hIAPP or drive self-assembly to the state of innocuous insoluble amyloid may be of potential therapeutic value. In this report we summarize key methods employed in our efforts to identify peptide-based modulators of amylin self-assembly that utilize π-electronic effects or electrostatic charge repulsion. These peptide-based modulators may serve as lead compounds for the development of more drug-like molecules and demonstrate that tuning π-electron density and employing charged amyloid disrupting elements are viable approaches toward the design of potential amyloid inhibitors.