TY - JOUR
T1 - Chemical Synthesis and Characterization of a Nonfibrillating Glycoglucagon
AU - Liu, Mengjie
AU - Zhao, Peishen
AU - Uddin, Md Hemayet
AU - Li, Wenyi
AU - Lin, Feng
AU - Chandrashekar, Chaitra
AU - Nishiuchi, Yuji
AU - Kajihara, Yasuhiro
AU - Forbes, Briony E.
AU - Wootten, Denise
AU - Wade, John D.
AU - Hossain, Mohammed Akhter
PY - 2021/10/20
Y1 - 2021/10/20
N2 - 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.
AB - 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.
KW - Serum
KW - Peptides and proteins
KW - Monomers
KW - Aggregation
KW - Post-translational modification
UR - http://www.scopus.com/inward/record.url?scp=85115611798&partnerID=8YFLogxK
U2 - 10.1021/acs.bioconjchem.1c00419
DO - 10.1021/acs.bioconjchem.1c00419
M3 - Article
AN - SCOPUS:85115611798
VL - 32
SP - 2148
EP - 2153
JO - Bioconjugate Chemistry
JF - Bioconjugate Chemistry
SN - 1043-1802
IS - 10
ER -