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| Targets |
GLP-2R[3]
GLP-2 receptor (GLP-2R). Glepaglutide is a long-acting GLP-2 analog that acts as a potent agonist of the glucagon-like peptide-2 receptor (GLP-2R), a G protein-coupled receptor primarily expressed in the gastrointestinal tract (intestine, stomach) as well as in the central nervous system. Activation of GLP-2R by glepaglutide promotes intestinal growth by stimulating crypt cell proliferation and inhibiting enterocyte apoptosis, leading to increased villus height and enhanced intestinal barrier function. GLP-2R activation also increases nutrient absorption, reduces gastric emptying, and decreases intestinal permeability, contributing to the therapeutic effects in short bowel syndrome. |
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| ln Vitro |
In vitro, glepaglutide acetate acts as a potent GLP-2R agonist. Cell-based assays using GLP-2R-expressing cells (e.g., HEK293 cells stably expressing human GLP-2R) demonstrate that glepaglutide activates the receptor with high potency, inducing cAMP accumulation. The compound shows enhanced stability in the presence of DPP-4 compared to native GLP-2. At the molecular level, glepaglutide promotes proliferation of intestinal epithelial cell lines (e.g., IEC-6 cells) in a concentration-dependent manner, with EC50 values in the low nanomolar range. Glepaglutide also inhibits serum starvation-induced apoptosis in intestinal cells, consistent with GLP-2R-mediated survival signaling.
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| ln Vivo |
In rats with minor intestinal inflammation, glepaglutide (ZP1848; 200 and 400 nmol/kg; subcutaneous injection; twice daily; for 14 days) acetate exhibited enterotrophic effects [3].
In vivo, glepaglutide acetate reduces fecal output and increases intestinal absorption. In rodent models of short bowel syndrome (SBS), subcutaneously administered glepaglutide (0.1-1 mg/kg) increases intestinal wet weight, villus height, and crypt depth in the residual small intestine, improving nutrient absorption and reducing diarrhea. The compound also alleviates inflammation in the small intestine. In animal models of colitis, glepaglutide reduces disease activity index and histological damage. Its long-acting nature (once-weekly dosing) has been demonstrated in pharmacokinetic/pharmacodynamic studies, where a single injection provides sustained body weight improvement and intestinal adaptation for up to 7 days in rats. |
| Enzyme Assay |
For direct binding assays, surface plasmon resonance (SPR) can be performed. Recombinant human GLP-2R (or GLP-2R-enriched membrane preparations) is immobilized onto a sensor chip. Glepaglutide acetate at concentrations ranging from 0.1 nM to 1 uM is flowed over the surface, and binding affinity (KD) is determined. A typical radioligand binding assay: membranes from CHO-K1 cells expressing human GLP-2R (0.5-2 ug protein/well) are incubated with 0.05 nM 125I-GLP-2 and varying concentrations of unlabeled glepaglutide acetate (0.01-1000 nM) in binding buffer (50 mM HEPES pH 7.4, 5 mM MgCl2, 1 mM CaCl2, 0.2% BSA, 20 ug/mL bacitracin) for 90-120 minutes at 25degC. Bound radioligand is separated by filtration through GF/B filters pre-soaked in 0.3% polyethyleneimine, and radioactivity is counted. IC50 and Ki values are calculated using nonlinear regression.
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| Cell Assay |
For cellular functional assays, HEK293 cells stably expressing human GLP-2R are seeded in 96-well plates at 2-5 × 10^4 cells/well in DMEM supplemented with 10% FBS. After 24 hours, culture medium is replaced with serum-free DMEM containing 0.5 mM IBMX. Glepaglutide acetate is added at concentrations ranging from 0.1 pM to 1 uM (10-fold serial dilutions) and incubated for 30 minutes at 37degC. Cells are lysed, and intracellular cAMP levels are quantified using a homogeneous time-resolved fluorescence (HTRF) or chemiluminescence-based cAMP detection kit. The EC50 value is derived from a sigmoidal dose-response curve using four-parameter logistic regression. For proliferation assays, IEC-6 rat intestinal epithelial cells are treated with glepaglutide acetate (0.1-100 nM) for 48-72 hours, and cell numbers are assessed by MTT or crystal violet staining.
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| Animal Protocol |
Animal/Disease Models: Rats with Indomethacin induced small intestinal inflammation[3]
Doses: 200 and 400 nmol/kg Route of Administration: Subcutaneousinjection (sc), twice a day for 14 days Experimental Results: Increased plasma citrulline concentration. Increased small intestinal mass. diminished small intestinal concentrations of the inflammatory marker (AGP and MPO). For in vivo efficacy studies, adult male Sprague-Dawley rats (250-300 g) or C57BL/6 mice are used. Glepaglutide acetate is formulated in sterile saline or PBS and administered subcutaneously at doses of 0.01-1 mg/kg, either as a single dose or once weekly for 2-4 weeks. Body weight and food intake are monitored daily. For intestinal adaptation studies in SBS models, rats undergo 75-80% small bowel resection. Glepaglutide acetate is administered subcutaneously for 7-14 days post-resection. At sacrifice, small intestine is removed, and segments are fixed for histological analysis (villus height, crypt depth measured on H&E-stained sections by light microscopy). Fecal output is collected over 24-48 hours using metabolic cages and weighed after drying. For intestinal permeability assessment, FITC-dextran (4 kDa, 500 mg/kg) is orally gavaged, and plasma FITC fluorescence is measured after 4 hours. |
| ADME/Pharmacokinetics |
Glepaglutide is engineered to be resistant to DPP-4 degradation, giving it a significantly prolonged half-life. In preclinical species (rats, dogs), the terminal half-life after subcutaneous administration is approximately 10-12 hours, supporting once-daily or every-other-day dosing. In clinical studies, glepaglutide has demonstrated a half-life of approximately 30 hours in humans, allowing for twice-weekly administration. The compound is absorbed slowly from subcutaneous injection sites, with Tmax of 4-8 hours. Clearance occurs primarily via renal and metabolic pathways. The acetate salt form does not substantially alter the intrinsic pharmacokinetic properties of the peptide. No drug-drug interaction studies have been reported.
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| Toxicity/Toxicokinetics |
No specific toxicity data are available for glepaglutide acetate. As a GLP-2R agonist, potential adverse effects are primarily gastrointestinal (abdominal pain, nausea, diarrhea, flatulence) as observed with other GLP-2 analogs (e.g., teduglutide). In animal toxicology studies with other GLP-2 analogs at supratherapeutic doses, no genotoxicity, carcinogenicity, or organ toxicity has been observed. GLP-2 analogs are generally well-tolerated with chronic administration. The acetate salt is widely used in pharmaceutical formulations and is considered non-toxic. Glepaglutide acetate is for research use only and not for human therapy without appropriate regulatory approvals.
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| References |
[1]. Naimi RM, et al. a novel long-acting glucagon-like peptide-2 analogue, for patients with short bowel syndrome: a randomised phase 2 trial. Lancet Gastroenterol Hepatol. 2019 May;4(5):354-363.
[2]. Janssen P, et al. Review article: a comparison of glucagon-like peptides 1 and 2. Aliment Pharmacol Ther. 2013 Jan;37(1):18-36. [3]. Jolanta Skarbaliene, et al. ZP1848, a Novel GLP-2 Agonist, Provides a Wide Window of Therapeutic Efficacy in the Experimental Crohn's Disease Model. Gastroenterology, 2011, 140(5): S519. |
| Additional Infomation |
GLP-2 (glucagon-like peptide-2) is a 33-amino acid peptide hormone produced by intestinal L-cells in response to nutrient ingestion. Native GLP-2 has a very short half-life (approximately 7 minutes) due to rapid degradation by DPP-4. Glepaglutide (ZP1848) is a long-acting GLP-2 analog developed by Zealand Pharma. While teduglutide is an approved GLP-2 analog for short bowel syndrome (SBS) requiring daily injection, glepaglutide was designed for less frequent (twice-weekly) administration. As of 2026, glepaglutide has been investigated in clinical trials for SBS and Crohn's disease but has not received regulatory approval. The acetate salt form is for research applications. Glepaglutide acetate reduces fecal output, increases intestinal absorption and reduces small intestinal inflammation.
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| Molecular Formula |
C199H329N53O57
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| Molecular Weight |
4376.13
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| Related CAS # |
Glepaglutide;914009-86-2
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| Appearance |
Typically exists as solid at room temperature
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
H2O :~100 mg/mL (~22.85 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.2285 mL | 1.1426 mL | 2.2851 mL | |
| 5 mM | 0.0457 mL | 0.2285 mL | 0.4570 mL | |
| 10 mM | 0.0229 mL | 0.1143 mL | 0.2285 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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