26. Chemical Synthesis and Characterization of a Nonfibrillating Glycoglucagon

Abstract:

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.

Liu, M.; Zhao, P.; Uddin, M. H.; Li, W.; Lin, F.; Chandrashekar, C.; Nishiuchi, Y.; Kajihara, Y.; Forbes, B.; Wootten, D.; Wade, D. J.; Hossain, M. A.* (2021), Chemical synthesis and characterization of a nonfibrillating glycoglucagon, Bioconjug Chem, 32, 10, 2148–2153, DOI: 10.1021/acs.bioconjchem.1c00419