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Similar content being viewed by others Introduction Unimolecular dual agonists for the glucagon-like peptide 1 receptor (GLP1R) and glucagon receptor (GCGR) are emerging as a potential new class of therapeutics in type 2 diabetes (T2D) 1,2,3 and Non-Alcoholic Steato Hepatitis (NASH) 4,5,6
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Intriguingly, even with similar drug exposures, women have been reported to experience more undesired effects of the semaglutide treatment compared to men (86)
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The critical design decisions included: GIP backbone selection : Starting from GIP rather than GLP-1, as GIP naturally has weak cross-reactivity with GLP-1R, providing a scaffold for optimization Aib2 substitution : Replacing Ala2 with alpha-aminoisobutyric acid for DPP-4 resistance (identical strategy to semaglutide) C-terminal extension : Adding a GGPSSGAPPPS (Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser) 11-residue C-terminal extension that enhances GLP-1R binding C-20 fatty diacid acylation : Attaching an eicosanedioic acid (C-20 diacid) at Lys20 via a Glu-2xOEG linker for albumin binding The resulting molecule exhibits approximately 5:1 selectivity for GIPR over GLP-1R it is a full GIPR agonist and a partial GLP-1R agonist, yet clinically achieves superior outcomes to selective full GLP-1R agonists [7]
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