Indiana University, Department of Chemistry, Bloomington, IN 47405, USA.
Mol Metab. 2014 Jan 22;3(3):293-300. doi: 10.1016/j.molmet.2014.01.006. eCollection 2014 Jun.
For more than half a century glucagon has been used as a critical care medicine in the treatment of life-threatening hypoglycemia. It is commercially supplied as a lyophilized powder intended to be solubilized in dilute aqueous hydrochloric acid immediately prior to administration. We have envisioned a "ready-to-use" glucagon as a drug of more immediate and likely use. Through a series of iterative changes in the native sequence we have identified glucagon analogs of appreciably enhanced aqueous solubility at physiological pH, and of chemical stability suitable for routine medicinal use. The superior biophysical properties were achieved in part through adjustment of the isoelectric point by use of a C-terminal Asp-Glu dipeptide. The native glutamines at positions 3, 20 and 24 as well as the methionine at 27 were substituted with amino acids of enhanced chemical stability, as directed by a full alanine scan of the native hormone. Of utmost additional importance was the dramatically enhanced stability of the peptide when Ser16 was substituted with alpha,aminoisobutyric acid (Aib), a substitution that stabilizes peptide secondary structure. The collective set of changes yield glucagon analogs of comparable in vitro and in vivo biological character to native hormone but with biophysical properties much more suitable for clinical use.
半个多世纪以来，胰高血糖素一直被用作治疗危及生命的低血糖的重要急救药物。它以冻干粉末的形式供应，旨在使用前在稀盐酸中溶解。我们设想了一种“即用型”胰高血糖素，它更即时，更可能被使用。通过对天然序列进行一系列的迭代改变，我们发现了一些胰高血糖素类似物，它们在生理 pH 值下具有明显增强的水溶性，并且具有适合常规药用的化学稳定性。通过使用 C 末端 Asp-Glu 二肽来调节等电点，部分实现了优越的生物物理性质。位置 3、20 和 24 的天然谷氨酰胺以及 27 位的蛋氨酸被增强化学稳定性的氨基酸取代，这是根据天然激素的全丙氨酸扫描来指导的。最重要的是，当 Ser16 被α-氨基异丁酸（Aib）取代时，肽的稳定性大大增强，这种取代稳定了肽的二级结构。这一系列的变化产生了与天然激素具有相当体外和体内生物学特征的胰高血糖素类似物，但具有更适合临床使用的生物物理性质。
