Department of Chemistry, Indiana University, Bloomington, Indiana 47405, United States.
ACS Chem Biol. 2013 Aug 16;8(8):1822-9. doi: 10.1021/cb4002624. Epub 2013 Jun 18.
A series of novel, single chain insulin analogs containing polyethylene glycol based connecting segments were synthesized by native chemical ligation and tested for biological activity. While the full length single chain insulin analogs exhibited low potency, deletion of amino acids B26-B30 unexpectedly generated markedly higher activity. This observation is unprecedented in all previous studies of single chain insulin analogs and is consistent with the presumption that in the native hormone this sequence must translocate to achieve high potency insulin receptor interaction. Optimization of the sequence yielded an insulin analog with potency and selectivity comparable to that of native insulin. These results establish a basis for discovery of novel higher potency, single chain insulin analogs of shortened length.
一系列新型的、含有聚乙二醇连接链段的单链胰岛素类似物通过天然化学连接合成，并测试了它们的生物活性。虽然全长的单链胰岛素类似物表现出低效力，但出人意料的是，缺失 B26-B30 氨基酸序列反而产生了更高的活性。这一观察结果在之前所有关于单链胰岛素类似物的研究中都是前所未有的，与这样的假设一致，即在天然激素中，该序列必须易位才能实现与胰岛素受体的高效相互作用。对该序列的优化得到了一种胰岛素类似物，其效力和选择性可与天然胰岛素相媲美。这些结果为发现新型、短链、高效力的单链胰岛素类似物奠定了基础。
