Tirzepatide – Dual GIP/GLP-1 Receptor Agonist

Chemical Identity

Chemical Name: Tirzepatide Acetate
Molecular Formula: C₂₂₇H₃₆₈N₄₈O₆₈
Molecular Weight: ~4813.5 Da
CAS Number: 2023788-19-2
Sequence (Linear): Y-Ahx-HGEGTFTSDLSKQMEEEAVRLFIEWLMNTKRNRNNIA-NH₂ (with fatty acid side chain)
Modifications: C20 fatty diacid moiety via γ-glutamic acid linker at Lys20
Structure Type: Synthetic linear peptide, 39 amino acids

Pharmacological Classification

Tirzepatide is a dual incretin mimetic that acts as a balanced agonist of the glucose-dependent insulinotropic polypeptide (GIP) receptor and a biased agonist of the glucagon-like peptide-1 (GLP-1) receptor, both of which are class B G protein-coupled receptors (GPCRs).

Mechanism of Action

• GIPR Activation: Enhances insulin secretion and lipogenesis in adipocytes.
• GLP-1R Activation: Inhibits glucagon, delays gastric emptying, and reduces appetite via CNS.
• Signaling: Activates cAMP via G_s proteins; exhibits GLP-1R biased agonism favoring cAMP over β-arrestin recruitment.

β-Arrestin Recruitment

Tirzepatide shows functionally selective (biased) agonism at GLP-1R and GIPR:

• GLP-1R: Compared to native GLP-1, tirzepatide demonstrates significantly reduced β-arrestin recruitment, favoring prolonged cAMP signaling and decreased receptor internalization. This may contribute to sustained therapeutic activity and reduced desensitization.
• GIPR: Tirzepatide retains strong G_s-coupled cAMP activation with moderate β-arrestin recruitment, aligning closely with endogenous GIP signaling dynamics.

Comparative β-Arrestin Profile

Receptor	Native Ligand	β-Arrestin Recruitment	Tirzepatide Activity
GLP-1R	GLP-1	High	Low (biased toward cAMP)
GIPR	GIP	Moderate	Similar

References: Lucey M et al., J Biol Chem 2020;295(45):15777–89. Willard FS et al., Cell Reports 2020;33(6):108293.

Molecular Engineering

Fatty acid conjugation increases albumin binding and plasma half-life. Sequence design includes DPP-IV resistance and selective receptor engagement with altered pharmacodynamics.

Pharmacokinetics (Non-Dosing)

• Elimination: Primarily proteolytic cleavage; renal excretion of fragments.
• Plasma Protein Binding: ~99%, primarily albumin
• Half-Life: ~5 days

Biological Effects

Modulates pancreatic hormone secretion, appetite, and adipocyte metabolism. Sustained receptor signaling contributes to glycemic control and weight reduction in preclinical models.

Preclinical Evidence

Demonstrated superior metabolic outcomes compared to GLP-1 monotherapy in db/db and high-fat diet models. Dual receptor activation provides enhanced insulinotropic response and fat mass reduction.

Stability and Storage

• Form: Lyophilized powder
• Solubility: Sterile water, acetate buffer, DMSO (analytical prep)
• Storage: –20°C, protected from light and moisture
• Reconstitution pH Range: 4.0–6.0 preferred

Comparative Mechanistic Summary

Parameter	GIP (native)	GLP-1 (native)	Tirzepatide
Receptor Affinity	High (GIPR)	High (GLP-1R)	Dual, moderate
β-arrestin Recruitment	Moderate	High	Low (GLP-1R)
Receptor Internalization	Yes	Rapid	Delayed
Half-life	Minutes	Minutes	~5 days
Albumin Binding	None	None	Strong

References

1. Yabe D, Seino Y. Prog Biophys Mol Biol. 2011;107(2):248–256.
2. Lucey M, et al. J Biol Chem. 2020;295(45):15777–15789.
3. Willard FS, et al. Cell Reports. 2020;33(6):108293.
4. Coskun T, et al. Diabetes. 2018;67(Suppl 1):64-LB.
5. Knudsen LB, Lau J. Front Endocrinol. 2019;10:155.
6. Secher A, et al. Brain Res. 2014;1587:87–93.
7. Finan B, et al. Cell Metab. 2021;33(1):77–91.
8. Zhao P, et al. Nat Commun. 2022;13:6921.