Amycretin: Molecular Structure
Chemical properties, amino acid sequence, and structural analysis
📌TL;DR
- •Molecular formula: C343H550N94O116
- •Molecular weight: 8000 Da
- •Half-life: Supports once-weekly SC dosing and once-daily oral dosing via albumin binding from C18 diacid sidechain
Amino Acid Sequence
127 amino acids
Formula
C343H550N94O116
Molecular Weight
8000 Da
Half-Life
Supports once-weekly SC dosing and once-daily oral dosing via albumin binding from C18 diacid sidechain
Molecular Structure and Properties#
Amycretin (NNC0487-0111) is a 68-amino-acid unimolecular peptide with a molecular weight of approximately 8 kDa and the molecular formula C343H550N94O116. It is the first-in-class molecule designed to activate both GLP-1 and amylin receptors as a single peptide entity.
Structural Architecture#
Amycretin is composed of two functional moieties within a single peptide chain:
- GLP-1 receptor agonist moiety: Located in the N-terminal region, designed for GLP-1 receptor activation
- Amylin receptor agonist moiety: Located in the C-terminal region, designed for amylin receptor activation
- Linker region: The two moieties are connected by a linker consisting of four glycine residues and one glutamate residue
Key Structural Modifications#
| Modification | Purpose |
|---|---|
| C18 diacid sidechain (at Lys37) | Reversible albumin binding for extended half-life |
| 2-Aminoisobutyric acid (Aib) | DPP-4 resistance at N-terminal GLP-1 sequence |
| C-terminal amidation | Peptide stability |
| Glycine-glutamate linker | Connects GLP-1 and amylin moieties |
Chemical Properties#
| Property | Value |
|---|---|
| Chemical class | Unimolecular dual agonist peptide |
| Amino acid count | 68 |
| Molecular weight | ~8 kDa |
| Molecular formula | C343H550N94O116 |
| CAS number | Not publicly disclosed |
| Receptor targets | GLP-1R and amylin receptor (CTR/RAMP complex) |
| SC dosing | Once weekly |
| Oral dosing | Once daily (with SNAC enhancer) |
Half-Life Extension#
The C18 diacid-based sidechain at position Lys37 enables reversible albumin binding in the circulation. This albumin binding:
- Extends the systemic half-life sufficiently for once-weekly SC dosing
- Protects against renal clearance
- Allows once-daily oral dosing (with appropriate formulation)
This is analogous to the acylation strategy used in semaglutide (C18 fatty diacid) and liraglutide (C16 fatty acid).
DPP-4 Resistance#
The introduction of 2-aminoisobutyric acid (Aib), an unnatural amino acid, in the N-terminal region of the GLP-1 sequence protects against dipeptidyl peptidase-4 (DPP-4) enzymatic degradation. This is the same strategy used in semaglutide.
Oral Formulation#
The oral tablet formulation of amycretin incorporates salcaprozate sodium (SNAC) as a permeation enhancer. SNAC is the same absorption enhancer used in oral semaglutide (Rybelsus). It temporarily increases gastric pH and enhances transcellular absorption of the peptide.
Pharmacokinetics#
Key pharmacokinetic observations from clinical trials:
- SC formulation: Once-weekly dosing supports sustained weight loss, indicating a terminal half-life of several days
- Oral formulation: Once-daily dosing with SNAC; achieves clinically meaningful systemic exposure
- Dose proportionality: Dose-dependent weight loss observed across multiple dose cohorts
- No plateau: Progressive weight loss without plateau at higher doses over 36 weeks
Comparison with CagriSema and Tirzepatide#
| Feature | Amycretin | CagriSema | Tirzepatide |
|---|---|---|---|
| Molecular approach | Single peptide | Two-peptide combination | Single peptide |
| Size | 68 aa (~8 kDa) | ~37 aa + ~31 aa | 39 aa (~4.8 kDa) |
| Targets | GLP-1R + amylin R | GLP-1R + amylin R | GLP-1R + GIPR |
| Acylation | C18 diacid (Lys37) | Both components acylated | C20 diacid (Lys20) |
| Oral formulation | Yes (with SNAC) | No (SC only) | No (SC only) |
| Developer | Novo Nordisk | Novo Nordisk | Eli Lilly |
Receptor Pharmacology#
Amycretin activates:
- GLP-1 receptor: Direct agonism through the GLP-1 moiety
- Amylin receptor: Activation through the amylin moiety targeting the calcitonin receptor (CTR) complexed with receptor activity-modifying proteins (RAMPs), particularly CTR/RAMP1 and CTR/RAMP3 complexes
The relative potency at each receptor and any biased agonism characteristics have not been fully disclosed.
Related Reading#
Frequently Asked Questions About Amycretin
What type of peptide is Amycretin?
Amycretin (NNC0487-0111) is a first-in-class unimolecular GLP-1 and amylin receptor agonist developed by Novo Nordisk. Unlike CagriSema (two separate peptides), amycretin combines both activities in a single 68-amino-acid molecule. In Phase 1b/2a, subcutaneous amycretin achieved up to 24.3% weight loss at 36 weeks (60 mg) and 22% at 20 mg. Oral amycretin achieved up to 13.1% at 12 weeks. Phase 3 for obesity and T2D planned for 2026.
What is the half-life of Amycretin?
The reported half-life of Amycretin is Supports once-weekly SC dosing and once-daily oral dosing via albumin binding from C18 diacid sidechain. Half-life can vary depending on the route of administration, formulation, and individual factors. This information is based on available preclinical or pharmacokinetic data.
What is the amino acid sequence of Amycretin?
The amino acid sequence of Amycretin is 68-amino-acid unimolecular GLP-1/amylin receptor agonist with GLP-1 and amylin moieties connected by a glycine-glutamate linker. 68-amino-acid peptide (~8 kDa) with GLP-1 and amylin receptor agonist moieties, C18 diacid sidechain for albumin binding, Aib substitution for DPP-4 resistance, C-terminal amidation. This sequence determines its biological activity and binding properties.
How stable is Amycretin in storage?
Amycretin is typically supplied as a lyophilized powder for maximum stability. 68-amino-acid peptide (~8 kDa) with GLP-1 and amylin receptor agonist moieties, C18 diacid sidechain for albumin binding, Aib substitution for DPP-4 resistance, C-terminal amidation. When reconstituted, it should be stored refrigerated at 2-8 degrees C and protected from light. Lyophilized powder should be stored at -20 degrees C.
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