| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
||
| 5mg |
|
||
| 10mg |
|
||
| Other Sizes |
| Targets |
Dasiglucagon is a peptide analog that specifically targets and activates the glucagon receptor (GCGR), a G protein-coupled receptor (GPCR) primarily expressed in the liver, pancreas, and kidneys. Upon binding to the GCGR, dasiglucagon activates a Gs protein signaling cascade, leading to the activation of adenylate cyclase, increased intracellular cAMP, and subsequent activation of protein kinase A (PKA). This results in the stimulation of hepatic glycogenolysis (breakdown of glycogen to glucose) and gluconeogenesis (synthesis of glucose from non-carbohydrate precursors), as well as increased lipolysis in adipose tissue. The net effect is a rapid increase in blood glucose concentration. Dasiglucagon is a full agonist with high potency at the GCGR.
|
|---|---|
| ln Vitro |
Dasiglucagon acetate is a potent glucagon receptor agonist. In vitro, dasiglucagon shows high binding affinity to the human glucagon receptor. It stimulates cAMP production in cells expressing the GCGR with an EC50 comparable to native human glucagon, demonstrating full agonistic activity. In functional assays using primary human hepatocytes, dasiglucagon induces glycogenolysis and glucose output in a concentration-dependent manner. The compound is also stable in aqueous solution, unlike native glucagon, which has poor solubility and stability at neutral pH. This physicochemical property makes dasiglucagon suitable for a ready-to-use liquid formulation. In vitro studies confirm the absence of significant off-target activity at other peptide hormone receptors (e.g., GLP-1, GIP, secretin receptors).
|
| ln Vivo |
The dasiglucagon PK profile demonstrates a fast and dose-dependent rise in plasma levels[2]. Dasiglucagon dosage: 0.1 mg, 0.3 mg, 0.6 mg, 1.0 mg N 5 16 16 16 AUC0–30min (pmol*h/L) 99.4 (32.0) 302 (78.9) 444 (163) 884 (307) AUC0–360min (pmol*h/L) 451 (123) 1360 (166) 1630 (368) 4800 (697) AUC0–inf (pmol*h/L) 451 (123) 1360 (166) 2640 (365) 4810 (696) Cmax (pmol/L) 334 (113) 976 (208) 1570 (445) 2800 (767) tmax (h) 0.50 (0.5-0.6) 0.63 (0.3-0.8) 0.58 (0.5-1.7) 0.63 (0.3-0.8) t1/2 (h) 0.43 (0.07) 0.43 (0.07) 0.49 (0.14) 0.54 (0.17)
In vivo, dasiglucagon acetate has been extensively studied in preclinical animal models (rodents, dogs) and in clinical trials. In healthy animals and in streptozotocin (STZ)-induced diabetic animals (a model of type 1 diabetes), subcutaneous or intravenous administration of dasiglucagon produces a rapid and robust increase in plasma glucose levels, with peak glucose elevation occurring within 15-30 minutes. The duration of action is approximately 60-90 minutes, which is comparable to native glucagon. In preclinical models of severe insulin-induced hypoglycemia, dasiglucagon effectively and rapidly restores euglycemia, reducing the risk of seizure and coma. Dasiglucagon has a favorable safety profile, with no significant hemodynamic effects at therapeutic doses. |
| Enzyme Assay |
The in vitro binding and functional activity of dasiglucagon are characterized using radioligand competition binding and cAMP accumulation assays. For receptor binding assays, membranes from CHO-K1 cells stably expressing the human glucagon receptor are prepared. Membranes (10-50 microg protein) are incubated with 0.1 nM [125I]glucagon and increasing concentrations of dasiglucagon (0.1 pM - 1 microM) in binding buffer (50 mM HEPES pH 7.4, 5 mM MgCl2, 1 mM CaCl2, 0.5% BSA, 0.1% bacitracin) for 60 min at room temperature. Bound radioactivity is separated by filtration through GF/B filters presoaked in 0.3% PEI. Nonspecific binding is defined with 1 microM unlabeled glucagon. IC50 values are converted to Ki using the Cheng-Prusoff equation. For functional assays, CHO-K1 cells expressing the GCGR are seeded in 96-well plates (1 × 10⁴ cells/well) and incubated overnight. Cells are washed with PBS and incubated with 0.5 mM IBMX (phosphodiesterase inhibitor) for 10 min. Dasiglucagon is added at concentrations of 0.1 pM - 1 microM, and the cells are incubated for 30 min at 37degC. The reaction is stopped by lysis, and cAMP levels are measured using a homogeneous time-resolved fluorescence (HTRF) cAMP assay kit or an ELISA kit. The EC50 for cAMP production is calculated. Typically, dasiglucagon shows an EC50 of approximately 0.1-1 nM for cAMP accumulation.
|
| Cell Assay |
Cellular assays to assess the activity of dasiglucagon acetate are performed in primary human hepatocytes or in immortalized hepatocyte cell lines such as HepG2 or Huh7 cells. Cells are cultured in DMEM with 10% FBS at 37degC and 5% CO2. Prior to treatment, cells are serum-starved for 2 h. Dasiglucagon is dissolved in water or PBS and diluted in serum-free culture medium to concentrations ranging from 0.01 pM to 100 nM. Cells are treated for 15-30 min. Glucose output is measured by collecting the culture medium and using a glucose oxidase-based assay kit (e.g., Amplex Red glucose assay). Intracellular cAMP is measured by lysing cells in 0.1 M HCl, followed by acetylation and ELISA. As an alternative readout, phosphorylation of CREB (cAMP response element-binding protein) can be measured by Western blot using anti-phospho-CREB (Ser133) antibody. To evaluate glycogen breakdown, cells are pre-incubated with 14C-glucose to label glycogen, then treated with dasiglucagon, and 14C-glucose release into the medium is measured by liquid scintillation counting. Native human glucagon is used as a positive control. Dasiglucagon produces a comparable or slightly more potent response than native glucagon in these assays, confirming full agonism.
|
| Animal Protocol |
In vivo efficacy is evaluated in a rodent model of insulin-induced hypoglycemia. Male Sprague-Dawley rats (200-250 g) are fasted overnight (16 h) with free access to water. Hypoglycemia is induced by a single subcutaneous injection of regular human insulin (1-2 U/kg). Blood glucose is measured from the tail vein using a glucometer at baseline, and every 15 minutes thereafter. Once blood glucose falls below 50 mg/dL (or to a defined target of 40-50 mg/dL), dasiglucagon acetate (dissolved in sterile saline or PBS) is administered subcutaneously (0.01-0.1 mg/kg) or intravenously (0.001-0.01 mg/kg). Control groups receive vehicle (saline) or native glucagon (0.01-0.1 mg/kg). Blood glucose is measured at 15, 30, 45, 60, 90, and 120 minutes post-dosing. The primary endpoint is the time to reach blood glucose >70 mg/dL (recovery from hypoglycemia) and the peak glucose level. Dasiglucagon, at a dose of 0.02 mg/kg s.c., reverses insulin-induced hypoglycemia within 15-20 minutes, achieving a peak glucose of 150-200 mg/dL. The time to recovery is comparable or slightly faster than native glucagon at the same dose. In a large animal model (dogs), a similar protocol is used, with continuous glucose monitoring (CGM) to track glucose levels. Dasiglucagon has also been studied in pediatric models of hypoglycemia.
|
| ADME/Pharmacokinetics |
Dasiglucagon acetate is a synthetic peptide (Mw = 3441.67 g/mol) with improved solubility and stability in aqueous formulations compared to native glucagon. Native glucagon is unstable at neutral pH, requiring reconstitution from a lyophilized powder immediately before use. Dasiglucagon is formulated as a ready-to-use solution at pH 7.0-8.0, with stability demonstrated for 24 months at 2-8degC. After subcutaneous injection, dasiglucagon is rapidly absorbed, with a median Tmax of 15-30 minutes in humans. In phase 1 clinical studies, the PK parameters for dasiglucagon (0.6 mg s.c.) in healthy volunteers are: Cmax = 7-10 ng/mL, Tmax = 15-30 min, t½ = 15-25 min. The elimination half-life is short, reflecting rapid degradation by proteolytic enzymes (dipeptidyl peptidase-4, DPP-4) and renal clearance. The metabolism of dasiglucagon is similar to that of endogenous glucagon, with the peptide being broken down into inactive fragments and excreted. The absolute bioavailability is approximately 90-100% after s.c. injection, which is superior to native glucagon (absorption is more predictable due to the stable liquid formulation). The volume of distribution is limited to the extracellular fluid. No drug accumulation occurs with repeated dosing. Dasiglucagon has a low potential for drug-drug interactions because it is a peptide not metabolized by CYP450 enzymes.
|
| Toxicity/Toxicokinetics |
Dasiglucagon is generally well-tolerated in clinical trials. The most common adverse events are gastrointestinal in nature, including nausea, vomiting, and abdominal discomfort (incidence ~10-20%). These effects are similar to those observed with native glucagon and are related to the mechanism of action (glucagon relaxes gastrointestinal smooth muscle). Mild injection site reactions (erythema, pain, swelling) occur in <5% of patients. Serious adverse events are rare; no anaphylaxis has been reported. Cardiovascular effects (tachycardia, increased blood pressure) can occur but are usually transient and mild. In preclinical toxicology studies in rats and dogs, repeated subcutaneous administration of dasiglucagon for up to 28 days did not cause significant organ toxicity, no genotoxicity was observed in the Ames test, and no carcinogenicity studies have been conducted (as the drug is intended for occasional use in emergencies, not chronic daily use). In the congenital hyperinsulinism (CHI) indication, where dasiglucagon is administered as a continuous subcutaneous infusion for long-term use, more extensive safety data are available, showing no new safety signals. The no-observed-adverse-effect level (NOAEL) in animal studies is >0.5 mg/kg/day. Dasiglucagon should not be used in patients with pheochromocytoma (risk of severe hypertension). Standard laboratory safety precautions are adequate for handling the peptide powder.
|
| References |
[1]. Bo Xu, et al. Dasiglucagon: an effective medicine for severe hypoglycemia. Eur J Clin Pharmacol. 2021 Dec;77(12):1783-1790.
[2]. Ulrike Hövelmann, et al. Pharmacokinetic and Pharmacodynamic Characteristics of Dasiglucagon, a Novel Soluble and Stable Glucagon Analog. Diabetes Care. 2018 Mar;41(3):531-537. [3]. Yongjing Ju, et al. Dasiglucagon for treating severe hypoglycemia in patients with diabetes. Expert Rev Clin Pharmacol. 2022 Jul;15(7):799-803. |
| Additional Infomation |
Dasiglucagon acetate is a stable, ready-to-use glucagon analog. The compound is approved in the European Union (EU) and the United States (FDA approved in 2021) under the brand name Zegalogue® for the treatment of severe hypoglycemia in pediatric and adult patients with diabetes aged 6 years and older. Dasiglucagon was developed by Zealand Pharma. The recommended dose is 0.6 mg (adults) and 0.6 mg or 0.3 mg (pediatric) administered by subcutaneous injection (prefilled autoinjector or syringe). Zegalogue is available as a liquid formulation in a single-dose autoinjector (Zegalogue Pen) or pre-filled syringe. The drug is not recommended for use in patients with known hypersensitivity to glucagon or to any of the excipients. Common side effects include nausea, vomiting, headache, diarrhea, and injection site pain. Dasiglucagon is also under investigation for the treatment of congenital hyperinsulinism (CHI) in phase 3 trials. Dasiglucagon acetate (as the research compound) is available for research purposes. The acetate counterion is used to form the stable salt and to adjust pH for formulation. The product is for research use only when purchased as a reagent; clinical use requires prescription. Do not store the research-grade compound at room temperature; store as powder at -20degC, protected from light and moisture. Molecular formula: C154H226N38O52. The chemical structure is (His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr) with modifications for stability. The compound is soluble in dilute acetic acid and PBS at pH 4-5; for in vivo use, it is typically formulated in sterile water for injection with mannitol as an isotonicity agent and sodium hydroxide to adjust pH to approximately 7.0-8.5.
|
| Molecular Formula |
C154H226N38O52
|
|---|---|
| Molecular Weight |
3441.67
|
| Related CAS # |
Dasiglucagon;1544300-84-6
|
| Appearance |
White to off-white solid powder
|
| HS Tariff Code |
2934.99.9001
|
| 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)
|
| Solubility (In Vitro) |
H2O :~16.67 mg/mL (~4.84 mM)
|
|---|---|
| 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 | 0.2906 mL | 1.4528 mL | 2.9056 mL | |
| 5 mM | 0.0581 mL | 0.2906 mL | 0.5811 mL | |
| 10 mM | 0.0291 mL | 0.1453 mL | 0.2906 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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
