TyrB26位点改变的人类胰岛素类似物的化学合成与体外活性

摘要：为了研究人类胰岛素B链第26位的酪氨酸对胰岛素和受体之间的结合的影响，包括单独的氨基酸替换或化合物替换的不同的胰岛素类似物被合成，其中化合物替代的类似物的B链C末端都减少了4个氨基酸。在对它们与胰岛素受体的亲和力进行研究中，结果发现它们与胰岛素受体的亲和力没有丢失， HisB26类似物和N-MeHisB26类似物的结合能力与胰岛素相比改变不大，分别是胰岛素的72 %和107 %。N-MeGluB26类似物，AadB26类似物和Phe (4-carboxy) B26类似物的结合能力有很大的提高，分别是130 %, 234 %和160 %。

Elaboration of Human Insulin Superagonism through Site-Selective Replacement at TyrB26

The role of conserved insulin residues TyrB26 was studied to better understand the relationship between insulin and its receptor. Insulin analogues with a single amino acid substitution or single N-methylation of the peptide bond in the position B26 were all shortened in the C-terminus of the B-chain by four amino acids. The effect of modifications was followed by the binding to the human insulin receptor. From our results: [HistidineB26]-des-tetrapeptide-(B27-B30)-insulin -B26-amide and [N-MeHisB26]-des-tetrapeptide-(B27-B30)-insulin-B26-amide had no significant effect on the binding affinity and they showed binding affinity 72 and 107 % of that of human insulin respectively; [N-MeGluB26]-des-tetrapeptide-(B27-B30)-insulin-B26-amide, [AadB26]-des- tetrapeptide-(B27-B30)-insulin-B26-amide and [Phe(4-carboxyB26)]-des-tetrapeptide-(B27-B30)– insulin-B26-amide affected the potency highly positively in vitro studies; they showed binding affinity 130, 234, 160%, respectively, of that of human insulin.