Mazdutide: Molecular Structure

Molecular Structure Overview#

Mazdutide (IBI362/LY3305677) is a 33-amino acid synthetic peptide with a molecular formula of C210H322N46O67 and a molecular weight of 4563.10 Daltons. The CAS number is 2259884-03-0. The peptide is derived from the structure of human oxyntomodulin (OXM), the endogenous hormone produced by intestinal L-cells that naturally activates both GLP-1 and glucagon receptors.

Two key chemical modifications distinguish mazdutide from native oxyntomodulin and enable its use as a once-weekly therapeutic agent:

1. Position 2 Aib substitution: The natural alanine at position 2 is replaced with 2-aminoisobutyric acid (Aib), a non-natural alpha,alpha-disubstituted amino acid. This modification sterically hinders the active site of dipeptidyl peptidase-4 (DPP-4), the enzyme responsible for rapid inactivation of endogenous GLP-1 and glucagon. The Aib substitution dramatically extends the peptide's biological half-life.

2. C20 fatty diacid at Lys-20: A C20 (eicosanedioic acid) fatty diacid is covalently attached to the epsilon-amino group of lysine at position 20 through a hydrophilic polyethylene glycol (PEG)-containing linker. This fatty acid chain binds non-covalently to serum albumin (>99% protein binding), creating a circulating depot that protects the peptide from renal clearance and enzymatic degradation while slowly releasing free drug.

Amino Acid Sequence Analysis#

The complete amino acid sequence of mazdutide in three-letter code is:

H-His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Lys-Ala-Lys*-Glu-Phe-Val-Glu-Trp-Leu-Leu-Glu-Gly-Gly-Pro-Ser-Ser-Gly-OH

(*Lys-20 carries the C20 fatty diacid conjugation)

The sequence preserves the critical N-terminal histidine that is essential for receptor binding across the glucagon superfamily. The first approximately 29 residues share high sequence homology with both GLP-1 and glucagon, which enables dual receptor activation. The C-terminal extension (residues 30-33) differentiates the structure from both native GLP-1 (30 amino acids) and glucagon (29 amino acids).

Sequence Comparison with Related Peptides#

The N-terminal region of mazdutide shares significant homology with endogenous glucagon superfamily members:

The conserved His-1 is critical for receptor activation, as it directly engages the transmembrane domain of both GLP-1R and GCGR. The Aib modification at position 2 is the key pharmaceutical innovation that provides DPP-4 resistance while maintaining receptor binding.

C20 Fatty Acid Chemistry#

The C20 fatty diacid moiety is a key pharmaceutical innovation that enables the once-weekly dosing regimen. The eicosanedioic acid chain binds to fatty acid binding sites on human serum albumin (HSA) with high affinity, creating a non-covalent albumin-peptide complex. The albumin-bound fraction is protected from renal filtration and from most peptidases. Free drug slowly dissociates from albumin to interact with target receptors, creating a steady-state plasma concentration.

The choice of a C20 diacid (rather than shorter or longer chains) represents optimization between albumin binding strength, aqueous solubility, and pharmaceutical manufacturability. Similar fatty acid conjugation strategies are employed in semaglutide (C18 diacid) and tirzepatide (C20 diacid).

Structural Basis for Dual Receptor Activation#

GLP-1 Receptor Binding#

The N-terminal portion of mazdutide (His-1 through approximately Glu-24) contains the primary determinants for GLP-1 receptor binding. Upon receptor engagement, residues 7-24 adopt an alpha-helical conformation that inserts into the binding cleft of the GLP-1 receptor extracellular domain. Key contact residues include Phe-6, Tyr-10, and Leu-14, which form hydrophobic interactions with the receptor core.

Glucagon Receptor Binding#

Glucagon receptor activation relies on the same N-terminal helical region but with different receptor contact points. The dual activity of mazdutide is achieved through careful optimization of the amino acid sequence to maintain productive interactions with both receptors. The balanced binding affinity (Ki = 17.7 nM for GCGR vs 28.6 nM for GLP-1R) reflects this optimization.

Pharmacokinetic Properties#

Absorption#

Following subcutaneous injection, mazdutide is slowly absorbed from the injection depot into systemic circulation. Peak plasma concentrations (Tmax) are typically reached 24-72 hours post-injection. The slow absorption rate, combined with albumin binding, contributes to the extended pharmacokinetic profile.

Distribution and Protein Binding#

Mazdutide is highly protein-bound (>99%), predominantly to serum albumin. This extensive protein binding limits the volume of distribution and provides the molecular basis for the extended half-life. Only the free (unbound) fraction is pharmacologically active.

Metabolism and Elimination#

The primary metabolic pathway involves proteolytic degradation after dissociation from albumin. The Aib substitution at position 2 protects against DPP-4 cleavage. The elimination half-life of approximately 4-6 days supports once-weekly dosing, with steady-state concentrations achieved after 4-5 weeks of weekly administration.

Physical and Chemical Properties#

Analytical Methods#

Mazdutide is quantified using validated LC-MS/MS methods. The unique molecular weight, fatty acid conjugation, and Aib residue provide distinctive analytical signatures. Quality control employs HPLC purity analysis, peptide content determination, and endotoxin testing for pharmaceutical preparations.

Related Reading#

• Mazdutide overview and research guide
• Peptides similar to Mazdutide
• Mazdutide research evidence