Glepaglutide: Molecular Structure
Chemical properties, amino acid sequence, and structural analysis
📌TL;DR
- •Molecular formula: C197H325N53O55
- •Molecular weight: 4235.11 Da
- •Half-life: ~88 hours effective half-life (10 mg SC dose)
Amino Acid Sequence
68 amino acids
Formula
C197H325N53O55
Molecular Weight
4235.11 Da
Half-Life
~88 hours effective half-life (10 mg SC dose)
Molecular Structure#
Glepaglutide (ZP1848) is a rationally designed synthetic analog of human glucagon-like peptide-2 (GLP-2) that overcomes the pharmacological limitations of the native hormone while enabling a novel ready-to-use liquid formulation. The design was published in the Journal of Medicinal Chemistry (PMID: 39851172), detailing how each modification contributes to the clinical profile.
Design Principles#
Native human GLP-2 is a 33-amino acid peptide that is:
- Rapidly degraded by DPP-IV (half-life ~7 minutes)
- Chemically unstable in aqueous solution (prone to oxidation and deamidation)
- Physically unstable (tendency to aggregate and fibrillate)
Glepaglutide addresses all three limitations through:
- Nine amino acid substitutions: Confer resistance to DPP-IV cleavage, reduce chemical degradation (oxidation, deamidation), and improve physical stability
- C-terminal hexalysine tail (SIP technology): The Structure Inducing Probe (SIP) technology adds six lysine residues at the C-terminus. This improves aqueous solubility and stability, enabling the ready-to-use liquid formulation, and also significantly improves synthetic yields
- No lipid modifications or disulfide bonds: Unlike many other long-acting peptide analogs (e.g., semaglutide with fatty acid chain, teduglutide with single-point mutation), glepaglutide achieves its extended action through a depot mechanism rather than albumin binding
Chemical Properties#
| Property | Value |
|---|---|
| Molecular weight | ~4,235 Da |
| Molecular formula | C197H325N53O55 |
| CAS number | 914009-86-2 |
| Length | 39 amino acids |
| Type | Linear synthetic GLP-2 analog |
| Disulfide bonds | None |
| Lipid modifications | None |
| C-terminal modification | Hexalysine (SIP) tail, amidated |
| Target | GLP-2 receptor (GLP-2R) |
| DPP-IV resistance | Engineered via amino acid substitutions |
Pharmacokinetics#
Glepaglutide exhibits unusual pharmacokinetics dominated by depot formation and metabolite activity:
Subcutaneous Depot Mechanism#
Following subcutaneous injection, glepaglutide forms a depot at the injection site. Two main metabolites are generated by C-terminal proteolytic cleavage:
- M1: 35-amino acid metabolite (loss of 4 C-terminal lysines)
- M2: 34-amino acid metabolite (loss of 5 C-terminal lysines)
Both M1 and M2 retain full GLP-2 receptor potency comparable to the parent compound. The slow release of these metabolites from the subcutaneous depot drives the extended pharmacological action.
Key PK Parameters#
| Parameter | Value |
|---|---|
| Effective half-life (10 mg SC) | ~88 hours (3.7 days) |
| Effective half-life (5 mg SC) | ~124 hours (5.2 days) |
| Predominant circulating species | M2 metabolite (~90% of exposure at steady state) |
| Parent drug exposure | Less than 1% of total exposure |
| Time to steady state | ~2-3 weeks with twice-weekly dosing |
| Absorption | Slow release from SC depot |
| Renal impairment effect | No dose adjustment required |
Pharmacodynamics#
The pharmacodynamic effects of glepaglutide include:
- Increased villus height and crypt depth (documented by histomorphometry)
- Increased intestinal blood flow (documented by CT angiography)
- Reduced fecal wet weight output
- Improved fluid and energy absorption
- Effects build over weeks to months as intestinal adaptation progresses
Comparison with Other GLP-2 Analogs#
| Feature | Native GLP-2 | Teduglutide | Glepaglutide | Apraglutide |
|---|---|---|---|---|
| Length | 33 aa | 33 aa | 39 aa | 33 aa (modified) |
| Key modification | None | Gly2 substitution | 9 substitutions + SIP tail | Fatty acid conjugation |
| Half-life | ~7 min | ~2 hours | ~88 hours | ~30 hours |
| Dosing | N/A | Daily | Twice weekly | Once weekly |
| Formulation | N/A | Lyophilized powder | Ready-to-use liquid | Lyophilized powder |
| Regulatory status | Endogenous | Approved (2012) | Phase 3 (CRL) | Phase 3 |
Stability#
Glepaglutide's defining structural advantage is its stability in aqueous solution. This is achieved without lipid modifications or chemical linkers, relying instead on the amino acid substitutions and SIP tail to prevent:
- Oxidation of methionine and tryptophan residues
- Deamidation of asparagine and glutamine residues
- Aggregation and fibrillation
This stability enables the ready-to-use autoinjector formulation, eliminating the reconstitution step required for teduglutide and reducing administration complexity for patients who may inject multiple times per week.
Related Reading#
Frequently Asked Questions About Glepaglutide
What type of peptide is glepaglutide?
Glepaglutide (ZP1848) is a 39-amino acid synthetic analog of human glucagon-like peptide-2 (GLP-2). It contains nine amino acid substitutions for DPP-IV resistance and chemical stability, plus a C-terminal hexalysine tail that enables stable aqueous formulation. Unlike many long-acting peptide analogs, it has no disulfide bonds, lipid modifications, or albumin-binding moieties.
What is the half-life of glepaglutide?
The effective half-life of glepaglutide is approximately 88 hours (about 3.7 days) for the 10 mg subcutaneous dose. This is achieved through slow release of pharmacologically active metabolites (M1 and M2) from the subcutaneous depot, not through fatty acid or albumin binding. This supports twice-weekly dosing.
How is glepaglutide different from native GLP-2?
Native GLP-2 is a 33-amino acid peptide with a half-life of approximately 7 minutes due to rapid DPP-IV cleavage. Glepaglutide has 39 amino acids (33 from GLP-2 plus a 6-lysine tail), nine amino acid substitutions for DPP-IV resistance and stability, and an effective half-life of about 88 hours. Glepaglutide is stable in aqueous solution, enabling a ready-to-use formulation.
How stable is glepaglutide in storage?
Glepaglutide is uniquely stable among GLP-2 analogs in aqueous solution, enabling a ready-to-use liquid formulation without reconstitution. This stability is conferred by the amino acid substitutions and the SIP hexalysine tail. Store refrigerated at 2-8 degrees C and protect from light.
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