Discovery of Insulin/GLP-1/Glucagon Triagonists for the Treatment of Diabetes and Obesity

The combination of insulin and incretin-based therapies
has emerged
as a potential promising tactic for the treatment of diabetes. Here
we report the first example of a unimolecular triagonist to simultaneously
target insulin, GLP-1, and glucagon receptors, aiming for better glycemic
control and superior weight loss. The strategy for constructing such
a unimolecular triagonist is the conjugation of the insulin moiety
and GLP-1R/GCGR coagonist peptide via alkyne–azide click chemistry.
Two tractable series differentiated by insulin conjugation sites,
B1F and B29K, were identified. Triagonist 13 prepared through the conjugation at insulin B1F and position 24 of GLP-1R/GCGR coagonist exhibited insulin activity
comparable to that of insulin degludec and potent and balanced GLP-1R
and GCGR activities. Pharmacokinetic profiles of 13 in
both rat and minipig were also discussed.