Sequence 3 letters:

Tyr-{Aib}-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile-{Aib}-Leu-Asp-Lys-Ile-Ala-Gln-{N6-{N-(hydrogen icosanedioyl)-γ-Glu-bis[iminobis(ethylenoxy)acetyl]}-Lys}-Ala-Phe-Val-Gln-Trp-Leu-Ile-Ala-Gly-Gly-Pro-Ser- Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2

Sequence:

YXEGTFTSDYSIXLDKIAQKAFVQWLIAGGPSSGAPPPS (X2 and X13 are α-amino isobutyric acid (Aib), S39 is L-serinamide, and K20 is N6-{N-(hydrogen icosanedioyl)-γ-Glu-bis[iminobis(ethylenoxy)acetyl]}-Lysine)

Cas No. :

Molecular Formula:

C₂₂₅H₃₄₈N₄₈O₆₈

Molecular Weight:

4813.45

Description

Tirzepatide (LY3298176) is a dual GIP and GLP-1 receptor agonist under development for the treatment of type 2 diabetes mellitus (T2DM), obesity, and nonalcoholic steatohepatitis. Early phase trials in T2DM indicate that tirzepatide improves clinical outcomes beyond those achieved by a selective GLP-1 receptor agonist. Tirzepatide was discovered by engineering GLP-1 activity into the GIP sequence. It is an imbalanced dual agonist in favor of GIPR over GLP-1R activity as the molecule shows equal affinity for the GIPR compared with native GIP but binds the GLP-1R with approximately 5-fold weaker affinity than native GLP-1. The imbalanced nature of tirzepatide may be critical to maximizing the efficacy of a dual agonist because dose escalation for GLP-1R activation can be limited by gastrointestinal effects such as nausea and vomiting, while GIPR engagement is not known to be associated with similar events. As a consequence, a pharmacological profile favoring potency at the GIPR offers an opportunity to fully engage this pathway while minimizing GLP-1–related tolerability issues. In addition to a potency ratio toward GIPR activity, tirzepatide contains a C20 unsaturated di-acid acyl chain to affect albumin binding, and the overall properties of the molecule enable once-weekly dosing. Beyond convenience, this pharmacokinetic feature may confer pharmacodynamic benefit, as high and sustained concentrations of selective GLP-1R agonists have enhanced clinical efficacy.

Reference

• Willard FS, Douros JD, Gabe MB, Showalter AD, Wainscott DB, Suter TM, et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight. 2020;5(17)
• Min T, Bain SC. The Role of Tirzepatide, Dual GIP and GLP-1 Receptor Agonist, in the Management of Type 2 Diabetes: The SURPASS Clinical Trials. Diabetes Ther. 2021;12(1):143-157
• Willard FS, Douros JD, Gabe MB, Showalter AD, Wainscott DB, Suter TM, et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight. 2020;5(17)