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首页> 外文期刊>Biochemistry >Rationally Designed, Nontoxic, Nonamyloidogenic Analogues of Human Islet Amyloid Polypeptide with Improved Solubility
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Rationally Designed, Nontoxic, Nonamyloidogenic Analogues of Human Islet Amyloid Polypeptide with Improved Solubility

机译：合理设计的人胰岛淀粉样多肽的无毒，无淀粉样生成的类似物，具有改善的溶解度

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Human islet amyloid polypeptide (hIAPP or amylin) is a polypeptide hormone produced in the pancreatic β-cells that plays a role in glycemic control. hIAPP is deficient in type 1 and type 2 diabetes and is a promising adjunct to insulin therapy. However, hIAPP rapidly forms amyloid, and its strong tendency to aggregate limits its usefulness. The process of hIAPP amyloid formation is toxic to cultured β-cells and islets, and islet amyloid formation in vivo has been linked to β-cell death and islet graft failure. An analogue of hIAPP with a weakened tendency to aggregate, denoted pramlintide (PM), has been approved for clinical applications, but suffers from poor solubility, particularly at physiological pH, and its unfavorable solubility profile prevents coformulation with insulin. We describe a strategy for rationally designing analogues of hIAPP with improved properties; key proline mutations are combined with substitutions that increase the net charge of the molecule. An H18R/G24P/I26P triple mutant and an H18R/A25P/S28P/S29P quadruple mutant are significantly more soluble at neutral pH than hIAPP or PM. They are nonamyloidogenic and are not toxic to rat INS β-cells. The approach is not limited to these examples; additional analogues can be designed using this strategy. To illustrate this point, we show that an S20R/G24P/I26P triple mutant and an H18R/I26P double mutant are nonamyloidogenic and significantly more soluble than human IAPP or PM. These analogues and second-generation derivatives are potential candidates for the coformulation of IAPP with insulin and other polypeptides.
机译：人胰岛淀粉样多肽（hIAPP或胰岛淀粉样多肽）是在胰腺β细胞中产生的多肽激素，在血糖控制中起作用。 hIAPP缺乏1型和2型糖尿病，是胰岛素治疗的有希望的辅助手段。然而，hIAPP迅速形成淀粉样蛋白，其强烈的聚集趋势限制了其实用性。 hIAPP淀粉样蛋白的形成过程对培养的β细胞和胰岛具有毒性，并且体内胰岛淀粉样蛋白的形成与β细胞死亡和胰岛移植失败有关。 hIAPP的聚集趋势较弱的类似物表示为普兰林肽（PM），已被批准用于临床，但其溶解性差，特别是在生理pH值时，溶解性差，其不利的溶解性会阻止与胰岛素共配制。我们描述了一种合理设计具有改进特性的hIAPP类似物的策略。关键的脯氨酸突变与增加分子净电荷的取代结合在一起。 H18R / G24P / I26P三重突变体和H18R / A25P / S28P / S29P四重突变体在中性pH下的溶解度明显高于hIAPP或PM。它们具有非淀粉样生成作用，并且对大鼠INSβ细胞无毒。该方法不限于这些示例。可以使用这种策略设计其他类似物。为了说明这一点，我们显示了S20R / G24P / I26P三重突变体和H18R / I26P双重突变体是非淀粉样生成的，并且比人IAPP或PM的溶解性更强。这些类似物和第二代衍生物是IAPP与胰岛素和其他多肽共同配制的潜在候选药物。

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