【摘要】 以可溶性长效胰岛素的工程化制备为目标,提出增加分子间次级键以稳化寡聚体产生长效性的原理,据此以精确的胰岛素三维结构为基础,进行了分子设计和计算机模拟,提出了对胰岛素的B链C端和N端修饰产生长效性的分子改造方案。以所获结果为指导,制备了两种目标产品:B2Lys—和B30Lys—胰岛素。对它们进行了生物学测试,表明确有长效性。这证明设计思想和改造方案是基本正确的,为进一步的蛋白质工程制备奠定了基础。更多还原

【Abstract】 In order to prapare soluble and prolonged-acting insulin derivatives, a principle for molecular design is proposed. The central idea of it is to make some non-covalent bonds between monomer of insulin oligamer so as to slow down the dissociation rate of insulin hexamer injected into the body and produce the protraction from a depot-effect. On the basis of this idea and the fine structure of insulin, molecular design and computer simulation are undertaken which provide some rational schemes for site-directed mutagenesis involving N- and C-terminal residues of B-chain. Among others, B2-Lys and B30-Lys insulins are semisynthesized as target samples respectively. The biological test in rabbits shows that both of them exhibite protracted glucose lowering effects. It demonstrates that both the idea for molecular design and the schemes for molecular modification are rational.更多还原