AI Article Synopsis
- The study introduces a novel unimolecular triagonist that combines insulin, GLP-1, and glucagon receptors for improved diabetes treatment and weight loss.
- The triagonist is created using alkyne-azide click chemistry, linking the insulin molecule with a coagonist peptide targeting GLP-1R and GCGR.
- The variations in the insulin conjugation sites were explored, with one specific triagonist showing promising activity comparable to current insulin treatments and effective receptor activities in animal models.
Article Abstract
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, B1 and B29, were identified. Triagonist prepared through the conjugation at insulin B1 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 in both rat and minipig were also discussed.
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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9377023 | PMC |
| http://dx.doi.org/10.1021/acsmedchemlett.2c00218 | DOI Listing |
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