一种长效胰岛素的分子设计和目标产品制备

Molecular Design and Target Sample Preparation for a Prolonged-acting Insulin

按照“增加次级键,稳化寡聚体”以产生长效性的分子设计原理,以精确的胰岛素三维结构为基础,通过计算机模拟提出对残基B2-Val→Lys/Arg的分子改造方案,并预测它能在不影响生物活力的条件下产生长效效应。在此基础上,用化学半合成的方法制备了目标产品desB1-LysB2胰岛素,并进行了产物活力和基本性质测定。结果表明,与天然胰岛素相比较,该目标产品保有基本的降血糖生物活力(82％),表现出显著的长效效应。

In order to prepare prolonged-acting insulin derivatives,a principle is proposed as : making-some additional non-covale-nt bonds between monomers and stabilizing the oligomer of insulin so as to cause the protracted action from a depot-effect. On basis of accurate three-dimensional structures designed schem of the mutation B2Val→Lys/Arg is rationally suggested. Computer simulation and modelling predicted that this kind of substitution will bring on a prolonged action and keep the substantial biological potency. On the guidance of this analysis,a derivative desBl-LysB2-Insulin is prepared by semisynthesis as a target product. Biological test and biochemical charecterization indicate that this target sample really exhibites a evidently prolonged action with a nearly full potency lowering blood glucose in rabbits. The posibility and the problem for the practical use of this sample are also discussed.