Tirzepatide (revision 5)
Old revision·08:58, 19 Jul 2024·AxisLabelAgda
| Tirzepatide | |
|---|---|
| INN | tirzepatide |
| Class | Dual incretin agonist (GIP/GLP-1) |
| Route | Subcutaneous, weekly |
| First approval | 2022 (type 2 diabetes) |
| Compound infobox · conventions | |
Tirzepatide is a 39-residue synthetic peptide that activates both the receptor for Glucose-dependent insulinotropic polypeptide and the GLP-1 receptor, making it the first dual incretin agonist to reach the market. Its backbone is derived from GIP rather than from GLP-1, and it is described in the literature as GIP-biased, with greater potency at the GIP receptor than at the GLP-1 receptor.[1]
Half-life extension follows the same logic as semaglutide: α-aminoisobutyric acid at positions 2 and 13 confers protease resistance, and a C-20 fatty diacid at Lys20 confers albumin binding. The resulting half-life of about five days supports weekly administration.[1]
Design and receptor pharmacology
[edit]Tirzepatide was built from the GIP sequence rather than from GLP-1, which is the reverse of the intuitive approach and reflects the finding that a GIP backbone tolerates the substitutions needed for GLP-1 activity better than the converse.[1]
Reported potency at the GIP receptor approaches that of native GIP, while potency at the GLP-1 receptor is roughly an order of magnitude below that of native GLP-1. The molecule is therefore not a balanced dual agonist, and the term "GIP-biased" is used in that sense. It also shows signalling bias at the GLP-1 receptor, favouring cAMP accumulation over β-arrestin recruitment; whether this contributes to the clinical effect is unresolved. See Receptor bias.