Cotadutide (MEDI0382): Molecular Structure

Molecular Overview#

Cotadutide (MEDI0382) is a 31-amino acid synthetic peptide designed as a dual GLP-1 and glucagon receptor agonist. Its structure is derived from oxyntomodulin, the endogenous dual-acting gut hormone, with significant modifications to improve potency, selectivity ratio, and pharmacokinetic properties.

Structural Design#

The molecular engineering of cotadutide involved several key modifications:

1. Oxyntomodulin-based backbone: The peptide sequence is based on the 37-amino acid oxyntomodulin, truncated and modified to optimize dual receptor engagement
2. Palmitic acid conjugation: An N-terminal C16 fatty acid is linked via a glutamic acid spacer, enabling non-covalent albumin binding that extends the half-life from minutes to approximately 11-13 hours
3. Internal amide bridge: A lactam bridge between Glu1 and Lys10 constrains the N-terminal alpha-helix, stabilizing the conformation required for balanced dual receptor agonism
4. GLP-1-biased selectivity: Strategic amino acid substitutions produce approximately 1.5-fold selectivity for GLP-1R over GCGR, ensuring that glycemic benefits from GLP-1 agonism counterbalance glucagon-mediated hyperglycemia

Physical and Chemical Properties#

Pharmacokinetics#

Cotadutide had a half-life of approximately 11-13 hours following subcutaneous injection, supporting once-daily dosing. The palmitic acid conjugation enabled albumin binding, extending the half-life compared to the unmodified parent peptide. While sufficient for daily dosing, this half-life was shorter than the ~7-day half-life achieved by semaglutide's C18 fatty diacid conjugation, which may have been a factor in AstraZeneca's decision to develop the weekly successor AZD9550.

Comparison with Related Dual Agonists#

Molecular Context#

Cotadutide (MEDI0382) belongs to the Metabolic category of research peptides. The molecular properties of Cotadutide (MEDI0382) determine its pharmacological behavior, including receptor binding, distribution, metabolism, and elimination. Understanding these properties is fundamental to interpreting clinical data and designing research protocols.

Structural Overview#

Cotadutide (MEDI0382) is characterized as: Cotadutide is a 31-amino acid synthetic peptide with a molecular weight of approximately 3,788 Da (acetate salt). Its design is based on the oxyntomodulin backbone, a natural dual GLP-1/glucagon agonist produced in intestinal L-cells. Key structural features include N-terminal palmitic acid (C16) conjugation for albumin binding and half-life extension, an internal amide bridge between positions 1 (Glu) and 10 (Lys) that constrains the N-terminal helix for improved receptor selectivity, and strategic amino acid substitutions to achieve GLP-1- biased dual agonism with EC50 of 6.9 pM at GLP-1R and 10.2 pM at GCGR..

Amino Acid Sequence Details#

The amino acid sequence of Cotadutide (MEDI0382) is: H-His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys-Ser-Glu-Tyr-Leu-Asp-Ser- Glu-Arg-Ala-Arg-Asp-Phe-Val-Ala-Trp-Leu-Glu-Ala-Gly-Gly-OH (31 amino acids). Contains N-terminal palmitic acid (C16) conjugation via the glutamic acid residue and an internal amide bridge between Glu1 and Lys10.. This sequence determines the peptide's three-dimensional structure, receptor binding properties, and biological activity.

Pharmacokinetic Profile#

Half-Life: ~11-13 hours, supporting once-daily subcutaneous injection

The half-life of a peptide influences dosing frequency, duration of effect, and the clinical utility of the compound. Researchers should consider the half-life when designing experimental protocols.

Related Reading#

• Cotadutide (MEDI0382) overview and research guide
• Peptides similar to Cotadutide (MEDI0382)
• Cotadutide (MEDI0382) research evidence