Chemical Synthesis and Characterization of a Nonfibrillating Glycoglucagon,Bioconjugate Chemistry

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Chemical Synthesis and Characterization of a Nonfibrillating Glycoglucagon
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2021-09-08 , DOI: 10.1021/acs.bioconjchem.1c00419
Mengjie Liu , Peishen Zhao ₁ , Md Hemayet Uddin ₂ , Wenyi Li , Feng Lin , Chaitra Chandrashekar , Yuji Nishiuchi _{3,

4} , Yasuhiro Kajihara ₅ , Briony E Forbes ₆ , Denise Wootten ₁ , John D Wade , Mohammed Akhter Hossain

Affiliation

The current commercially available glucagon formulations for the treatment of severe hypoglycemia must be reconstituted immediately prior to use, owing to the susceptibility of glucagon to fibrillation and aggregation in an aqueous solution. This results in the inconvenience of handling, misuse, and wastage of this drug. To address these issues, we synthesized a glycosylated glucagon analogue in which the 25th residue (Trp) was replaced with a cysteine (Cys) and a Br-disialyloligosaccharide was conjugated at the Cys thiol moiety. The resulting analogue, glycoglucagon, is a highly potent full agonist at the glucagon receptor. Importantly, glycoglucagon exhibits markedly reduced propensity for fibrillation and enhanced thermal and metabolic stability. This novel analogue is thus a valuable lead for producing stable liquid glucagon formulations that will improve patient compliance and minimize wastage.

中文翻译：

非纤维化糖高血糖素的化学合成和表征

由于胰高血糖素在水溶液中容易发生纤维化和聚集，目前市售的用于治疗严重低血糖的胰高血糖素制剂必须在使用前立即重新配制。这导致该药物处理、误用和浪费的不便。为了解决这些问题，我们合成了一种糖基化胰高血糖素类似物，其中第 25 个残基 (Trp) 被半胱氨酸 (Cys) 取代，并且 Br-二唾液酸寡糖在 Cys 硫醇部分缀合。由此产生的类似物，糖高血糖素，是一种高效的胰高血糖素受体完全激动剂。重要的是，糖高血糖素显着降低了纤维颤动的倾向，并增强了热稳定性和代谢稳定性。因此，这种新型类似物是生产稳定的液体胰高血糖素制剂的宝贵先导，可提高患者的依从性并最大限度地减少浪费。

更新日期：2021-10-20

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