Mazdutide – Dual GLP-1/Glucagon Receptor Agonist

Chemical Identity

Chemical Name: Mazdutide Acetate (also known as IBI362)
Molecular Formula: C₂₂₇H₃₆₄N₄₆O₆₇
Molecular Weight: ~4791.6 Da
CAS Number: 2416895-87-7
Sequence (Linear): GLP-1-based sequence with multiple amino acid substitutions and lipidation for prolonged activity
Modifications: C18 fatty diacid side chain conjugated via linker to lysine residue; engineered substitutions for enhanced dual GLP-1R/GCGR co-agonism
Structure Type: Synthetic 39-amino acid linear peptide, lyophilized acetate salt

Pharmacological Classification

Mazdutide is a **dual receptor agonist** that targets both the **glucagon-like peptide-1 receptor (GLP-1R)** and the **glucagon receptor (GCGR)**. Developed by Innovent Biologics, it is under clinical investigation for obesity and metabolic-associated fatty liver disease (MAFLD/MASH).

Mechanism of Action

• GLP-1R Activation: Increases glucose-dependent insulin secretion, suppresses glucagon, delays gastric emptying, and reduces appetite.
• GCGR Activation: Stimulates hepatic lipid oxidation, thermogenesis, and energy expenditure.
• Signal Transduction: Both receptors primarily signal through G_s protein → adenylyl cyclase → cAMP → PKA pathway.

β-Arrestin Recruitment

Mazdutide exhibits receptor-specific bias in β-arrestin recruitment:

• GLP-1R: Displays low β-arrestin recruitment relative to native GLP-1, favoring cAMP signaling and limiting internalization.
• GCGR: Exhibits moderate β-arrestin recruitment, balancing receptor signaling and desensitization.

Comparative β-Arrestin Profile

Receptor	Native Ligand	β-Arrestin Recruitment	Mazdutide Activity
GLP-1R	GLP-1	High	Reduced (biased toward cAMP)
GCGR	Glucagon	Moderate	Moderate

References: Lin L et al., eClinicalMedicine. 2023;62:102133. Willard FS et al., Cell Reports. 2020;33(6):108293.

Molecular Engineering

Modified with multiple substitutions to enhance dual receptor affinity. C18 fatty acid conjugation via a linker increases half-life and albumin binding. Designed to improve metabolic efficacy while reducing gastrointestinal side effects.

Pharmacokinetics (Non-Dosing)

• Elimination: Primarily via proteolysis; renal clearance of fragments
• Plasma Protein Binding: >99% (albumin-mediated)
• Half-Life: ~6–7 days

Biological Effects

Reduces body weight, appetite, and hepatic steatosis through GLP-1–mediated anorectic effects and GCGR-mediated energy expenditure. No hypoglycemia observed due to glucose-dependent insulinotropic activity.

Preclinical Evidence

In rodent and monkey models, Mazdutide significantly reduced food intake, body fat, liver triglycerides, and improved insulin sensitivity. Demonstrated robust synergy between GLP-1R and GCGR pathways.

Stability and Storage

• Form: Lyophilized powder, acetate salt
• Solubility: Water, low-pH buffers (pH 4.0–6.0), DMSO for in vitro work
• Storage: –20°C, light- and moisture-protected
• Reconstitution pH: 4.5–5.5 recommended

Comparative Mechanistic Summary

Parameter	GLP-1	Glucagon	Mazdutide
Receptor Targets	GLP-1R	GCGR	Both
β-arrestin Recruitment	High	Moderate	Low–Moderate
Half-Life	<5 minutes	~10 minutes	~6–7 days
Albumin Binding	No	No	Yes

References

1. Lin L, et al. eClinicalMedicine. 2023;62:102133.
2. Zhou J, et al. Front Endocrinol. 2022;13:944728.
3. Willard FS, et al. Cell Reports. 2020;33(6):108293.
4. Sun F, et al. Diabetes Obes Metab. 2023;25(5):1363–1372.