Retatrutide – Triple GIP/GLP-1/Glucagon Receptor Agonist

Chemical Identity

Chemical Name: Retatrutide Acetate
Molecular Formula: C₂₂₁H₃₄₃N₄₇O₆₇
Molecular Weight: ~4761.6 Da
CAS Number: 2762296-94-4
Sequence (Linear): Proprietary sequence engineered for balanced co-activation of GIPR, GLP-1R, and GCGR, with a C20 fatty diacid side chain at a lysine residue
Modifications: Multisite substitution and lipidation for DPP-IV resistance and extended circulation
Structure Type: Synthetic linear peptide, 39 amino acids, lyophilized acetate salt

Pharmacological Classification

Retatrutide is a **balanced triple agonist** of the GIP, GLP-1, and glucagon receptors. It represents a next-generation incretin-based therapeutic platform designed to maximize metabolic flexibility through multi-receptor synergy.

Mechanism of Action

• GIPR Activation: Enhances insulin secretion, adipocyte glucose uptake, and energy storage in a glucose-dependent manner.
• GLP-1R Activation: Suppresses appetite, increases satiety, slows gastric emptying, and improves β-cell responsiveness.
• GCGR Activation: Stimulates hepatic fatty acid oxidation and thermogenesis; increases energy expenditure.
• Signaling: All three receptors signal via G_s-mediated cAMP accumulation; downstream effects are receptor- and tissue-specific.

β-Arrestin Recruitment

Retatrutide exhibits tailored β-arrestin profiles across each of its three target receptors:

• GLP-1R: Acts as a biased agonist favoring cAMP production over β-arrestin recruitment, reducing receptor internalization and extending signaling duration.
• GIPR: Moderate β-arrestin recruitment consistent with endogenous GIP activity.
• GCGR: Exhibits balanced recruitment to support controlled receptor trafficking and avoid overstimulation.

Comparative β-Arrestin Profile

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

References: Kelly AS et al., NEJM 2023;389(7):621–632. Willard FS et al., Cell Reports 2020;33(6):108293. Nestorowicz T et al., bioRxiv 2023.

Molecular Engineering

Engineered through strategic residue substitutions and site-specific lipidation to optimize receptor binding, prolong half-life, and maintain GIPR/GLP-1R/GCGR signaling balance. DPP-IV-resistant design ensures metabolic stability.

Pharmacokinetics (Non-Dosing)

• Elimination: Hepatic and renal degradation of peptide fragments
• Plasma Protein Binding: >99% via albumin-binding fatty acid moiety
• Half-Life: ~5–6 days (estimated from Phase 1 data)

Biological Effects

Combines glycemic control (GLP-1/GIP) with weight loss and energy expenditure enhancement (GCGR). In animal and human studies, leads to reductions in body fat, fasting insulin, triglycerides, and hepatic steatosis.

Preclinical Evidence

In rodent DIO models and non-human primates, retatrutide reduced total body weight by up to 24%, exceeding effects of GLP-1 mono- or dual agonists. Demonstrated favorable cardiovascular and hepatic metabolic markers.

Stability and Storage

• Form: Lyophilized peptide acetate salt
• Solubility: Water, acetate buffer (pH 4–6), DMSO for analytical prep
• Storage: –20°C; protected from light and moisture
• Reconstitution pH: 4.0–5.5 preferred

Comparative Mechanistic Summary

Parameter	GLP-1	GIP	Glucagon	Retatrutide
Receptor Targets	GLP-1R	GIPR	GCGR	All three
β-arrestin Recruitment	High	Moderate	Moderate	Low–Moderate
Half-life	Minutes	Minutes	Minutes	~5–6 days
Albumin Binding	No	No	No	Yes

References

1. Kelly AS, et al. NEJM. 2023;389(7):621–632.
2. Nestorowicz T, et al. bioRxiv. 2023. doi:10.1101/2023.07.05.548892
3. Willard FS, et al. Cell Reports. 2020;33(6):108293.
4. Finan B, et al. Cell Metab. 2019;29(3):740–750.e10.
5. Coskun T, et al. Diabetes. 2018;67(Supplement_1):64-LB.