Insulins with built-in glucose sensors for glucose responsive insulin release
Insulins with built-in glucose sensors for glucose responsive insulin release
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DOI：
10.1002/psc.624
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发表时间：
2005-06-01
影响因子：
2.1
通讯作者：
Markussen, J
中科院分区：
文献类型：
--
作者：
Hoeg-Jensen, T;Ridderberg, S;Markussen, J
描述了用苯基硼酸衍生胰岛素，从而使胰岛素具有新的葡萄糖敏感能力。还证明了这种胰岛素可用于基于葡萄糖响应性聚合物的释放系统。优选的苯基硼酸是磺酰胺衍生物，与天然硼酸相反，其确保在生理pH下葡萄糖结合，并同时作为在LysB 29处胰岛素衍生化的手柄。通过葡萄糖滴定与茜素的竞争性测定中的葡萄糖亲和力的新的胰岛素进行了评价。亲和力在15-31 mm（Kd）范围内，这与生理葡萄糖波动相匹配。使用葡糖胺衍生的聚乙二醇聚丙烯酰胺（PEGA）作为模型，证明了新型胰岛素的剂量响应性葡萄糖介导的释放，并且表明硼化胰岛素的Zn（II）六聚体制剂相对于单体胰岛素制剂导致更陡的葡萄糖敏感性。值得注意的是，两种硼化胰岛素显示出相对于天然胰岛素增强的胰岛素受体亲和力（113%-122%），这对于胰岛素LysB 29衍生物是不寻常的。版权所有（c）2004欧洲肽协会和约翰威利父子有限公司。
Derivatization of insulin with phenylboronic acids is described, thereby equipping insulin with novel glucose sensing ability. it is furthermore demonstrated that such insulins are useful in glucose- responsive polymer-based release systems. The preferred phenylboronic acids are sulfonamide derivatives, which, contrary to naive boronic acids, ensure glucose binding at physiological pH, and simultaneously operate as handles for insulin derivatization at LysB29. The glucose affinities of the novel insulins were evaluated by glucose titration in a competitive assay with alizarin. The affinities were in the range 15-31 mm (Kd), which match physiological glucose fluctuations. The dose-responsive glucose-mediated release of the novel insulins was demonstrated using glucamine-derived polyethylene glycol polyacrylamide (PEGA) as a model, and it was shown that Zn(II) hexamer formulation of the boronated insulins resulted in steeper glucose sensitivity relative to monomeric insulin formulation. Notably, two of the boronated insulins displayed enhanced insulin receptor affinity relative to native insulin (113%-122%) which is unusual for insulin LysB29 derivatives. Copyright (c) 2004 European Peptide Society and John Wiley & Sons, Ltd.