THE COBALT(III)-INSULIN HEXAMER IS A PROLONGED-ACTING INSULIN PRODRUG
THE COBALT(III)-INSULIN HEXAMER IS A PROLONGED-ACTING INSULIN PRODRUG
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DOI：
10.1002/jps.2600841006
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发表时间：
1995-10-01
影响因子：
3.8
通讯作者：
SORENSEN, AR
中科院分区：
文献类型：
--
作者：
KURTZHALS, P;KIEHR, B;SORENSEN, AR
胰岛素六聚体有两个高亲和力金属离子结合位点，每个位点涉及三个 His(B10) 残基，每个二聚体各有一个。含有 Co2+ 的胰岛素六聚体在这两个位点都被氧化，形成稳定的 Co3+-胰岛素复合物。结果表明，Co3+配位的胰岛素单体在pH 8.0的水溶液中释放极其缓慢，并且六聚体在胰岛素纳摩尔浓度下不会自发解离成亚基。 Co3+-胰岛素六聚体在体外不被胰岛素受体识别，但该复合物在皮下 (sc) 注射到兔子体内后显示出持久的作用特征。 Co3+-胰岛素六聚体为可溶性长效胰岛素制剂提供了一种新颖的前药方法，可用于治疗糖尿病的基础胰岛素输送。
The insulin hexamer has two high-affinity metal ion binding sites, each involving three His(B10) residues, one from each dimer. Insulin hexamers containing Co2+ af both these sites were oxidized to form a stable Co3+-insulin complex. It is shown that the Co3+-coordinated insulin monomers are released extremely slowly in aqueous solution at pH 8.0, and that the hexamer does not spontaneously dissociate into subunits at nanomolar concentrations of insulin. The Co3+-insulin hexamer is not recognized by the insulin receptor in vitro but the complex shows a protracted action profile following subcutaneous (sc) injection into rabbits. The Co3+-insulin hexamer provides a novel prodrug approach to a soluble, prolonged-acting insulin preparation of potential use for basal insulin delivery in the treatment of diabetes.