Celgosivir hydrochloride (MBI 3253 (hydrochloride))
(Synonyms: MBI 3253 hydrochloride; MDL 28574 hydrochloride; MX3253 hydrochloride) 目录号 : GC32074
Celgosivir hydrochloride (MBI 3253 (hydrochloride)) (MBI 3253 hydrochloride; MDL 28574 hydrochloride; MX3253 hydrochloride) 是一种 α-葡萄糖苷酶 I 抑制剂；体外试验中抑制牛病毒性腹泻病毒 (BVDV)，IC50 为 1.27 μM。
Cas No.:141117-12-6
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cell experiment: | The cytotoxicity of Celgosivir is measured by the Cell titer-Glo Luminescent cell viability assay. The luminescence signals for cells treated with the test compounds are compared to those for cells treated with the maximum tolerated DMSO to determine the 50% cytotoxic concentration[3]. |
Animal experiment: | Mice: To model ADE, mice are injected i.p. with 20 μg /mouse of mouse monoclonal antibody against DENV E protein one day prior to infection. For treatment during infection, celgosivir (50 mg/kg) is injected i.p. twice daily for 5 days, starting from day 0, 1 or 2. Blood is collected at days 1, 3 and 7 by submandibular bleeding. Survival of mice is followed until day 10 and survival curves are plotted[3]. |
References: [1]. Taylor DL, et al. Inhibition of alpha-glucosidase I of the glycoprotein-processing enzymes by 6-O-butanoylcastanospermine (MDL 28,574) and its consequences in human immunodeficiency virus-infected T cells. Antimicrob Agents Chemother. 1994 Aug;38(8):1780-7. | |
Celgosivir hydrochloride (MDL 28574A) is an α-glucosidase I inhibitor; inhibits bovine viral diarrhoea virus (BVDV) with an IC50 of 1.27 μM in in vitro assay.
Celgosivir is more effective (IC50=20 μM) than the parent molecule (IC50=254 ,uM) at causing the accumulation of glucosylated oligosaccharides in HIV-infected cells by inhibition of glycoprotein processing. Celgosivir exhibits potent antiviral activity against HIV-1 with an IC50 of 2.0±2.3 μM[1]. Bovine viral diarrhoea virus (BVDV) is a closely related virus of hepatitis C virus (HCV). Celgosivir inhibits BVDV with IC50 values of 16 and 47 μM in plaque assay and cytopathic effect assay, respectively[2]. Celgosivir inhibits DENV2 replication with an EC50 of 0.2 μM. The EC50 values against DENV1, 3 and 4 are less than 0.7 μM[3].
Celgosivir fully protects AG129 mice from lethal infection with a mouse adapted dengue virus at a dose of 50 mg/kg twice daily (BID) for 5 days and is effective even after 48 h delayed treatment. The protection by celgosivir is dose- and schedule-dependent and that a twice-a-day regimen of 50, 25 or 10 mg/kg is more protective than a single daily dose of 100 mg/kg. Pharmacokinetics studies of celgosivir in mice shows that it rapidly metabolizes to castanospermine[4]. During primary infection with a mouse-adapted DENV strain S221, mice shows increased viremia on day 3, yet 80% survived day 10 with virus completely cleared by day 8[3].
[1]. Taylor DL, et al. Inhibition of alpha-glucosidase I of the glycoprotein-processing enzymes by 6-O-butanoylcastanospermine (MDL 28,574) and its consequences in human immunodeficiency virus-infected T cells. Antimicrob Agents Chemother. 1994 Aug;38(8):1780-7. [2]. Whitby K, et al. Action of celgosivir (6 O-butanoyl castanospermine) against the pestivirus BVDV: implications for the treatment of hepatitis C. Antivir Chem Chemother. 2004 May;15(3):141-51. [3]. Watanabe S, et al. Dose- and schedule-dependent protective efficacy of celgosivir in a lethal mouse model for dengue virus infection informs dosing regimen for a proof of concept clinical trial. Antiviral Res. 2012 Oct;96(1):32-5. [4]. Rathore AP, et al. Celgosivir treatment misfolds dengue virus NS1 protein, induces cellular pro-survival genes andprotects against lethal challenge mouse model. Antiviral Res. 2011 Dec;92(3):453-60.
| Cas No. | 141117-12-6 | SDF | |
| 别名 | MBI 3253 hydrochloride; MDL 28574 hydrochloride; MX3253 hydrochloride | ||
| Canonical SMILES | O[C@@H]1[C@]2([H])[C@@H](O)[C@H](O)[C@@H](OC(CCC)=O)CN2CC1.Cl[H] | ||
| 分子式 | C12H22ClNO5 | 分子量 | 295.76 |
| 溶解度 | Water : ≥ 200 mg/mL (676.22 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.3811 mL | 16.9056 mL | 33.8112 mL |
| 5 mM | 0.6762 mL | 3.3811 mL | 6.7622 mL |
| 10 mM | 0.3381 mL | 1.6906 mL | 3.3811 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Celgosivir, an alpha-glucosidase I inhibitor for the potential treatment of HCV infection
Curr Opin Investig Drugs 2009 Aug;10(8):860-70.PMID:19649930doi
Celgosivir, in development by MIGENIX Inc for the treatment of HCV infection, is an oral prodrug of the natural product castanospermine that inhibits alpha-glucosidase I, an enzyme that plays a critical role in viral maturation by initiating the processing of the N-linked oligosaccharides of viral envelope glycoproteins. Celgosivir is well absorbed in vitro and in vivo, and is rapidly converted to castanospermine. Celgosivir has a novel mechanism of action (ie, host-directed glycosylation), and demonstrates broad antiviral activity in vitro. The agent is not efficient as a monotherapy for the treatment of HCV, but has demonstrated a synergistic effect in combination with the current standard of care, PEGylated IFNalpha2b plus ribavirin, both in vitro and in phase II clinical trials. At the time of publication, a phase II trial was underway to investigate the safety, tolerability and antiviral effect of Celgosivir in combination with PEGylated IFNalpha2b plus ribavirin for up to 1 year in patients with chronic HCV infection. Celgosivir may prove to be a valuable component for combination therapy and may help to prevent the apparition of drug resistance. Long-term toxicity studies are necessary to confirm the safety of this novel drug in humans.
Celgosivir treatment misfolds dengue virus NS1 protein, induces cellular pro-survival genes and protects against lethal challenge mouse model
Antiviral Res 2011 Dec;92(3):453-60.PMID:22020302DOI:10.1016/j.antiviral.2011.10.002.
Dengue virus (DENV) infections continue to spread aggressively around the world. Here we demonstrate that Celgosivir (6-O-butanoyl castanospermine), strongly inhibits all four DENV serotypes. We show by fluorescence microscopy that the antiviral mechanism of Celgosivir, is in part, due to misfolding and accumulation of DENV non-structural protein 1 (NS1) in the endoplasmic reticulum. Moreover, Celgosivir modulates the host's unfolded protein response (UPR) for its antiviral action. Significantly, Celgosivir is effective in lethal challenge mouse models that recapitulate primary or secondary antibody-dependent enhanced DENV infection. Celgosivir treated mice showed enhanced survival, reduced viremia and robust immune response, as reflected by serum cytokine analysis. Importantly, survival increased even after treatment was delayed till 2 days post-infection. Together the present study suggests that Celgosivir, which has been clinically determined to be safe in humans, may be a valuable candidate for clinical testing in dengue patients.
The iminosugars Celgosivir, castanospermine and UV-4 inhibit SARS-CoV-2 replication
Glycobiology 2021 May 3;31(4):378-384.PMID:32985653DOI:10.1093/glycob/cwaa091.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic poses an unprecedented challenge for health care and the global economy. Repurposing drugs that have shown promise in inhibiting other viral infections could allow for more rapid dispensation of urgently needed therapeutics. The Spike protein of SARS-CoV-2 is extensively glycosylated with 22 occupied N glycan sites and is required for viral entry. In other glycosylated viral proteins, glycosylation is required for interaction with calnexin and chaperone-mediated folding in the endoplasmic reticulum, and prevention of this interaction leads to unfolded viral proteins and thus inhibits viral replication. As such, we investigated two iminosugars, Celgosivir, a prodrug of castanospermine, and UV-4, or N-(9-methoxynonyl)-1-deoxynojirimycin, a deoxynojirimycin derivative. Iminosugars are known inhibitors of the α-glucosidase I and II enzymes and were effective at inhibiting authentic SARS-CoV-2 viral replication in a cell culture system. Celgosivir prevented SARS-CoV-2-induced cell death and reduced viral replication and Spike protein levels in a dose-dependent manner in culture with Vero E6 cells. Castanospermine, the active form of Celgosivir, was also able to inhibit SARS-CoV-2, confirming the canonical castanospermine mechanism of action of Celgosivir. The monocyclic UV-4 also prevented SARS-CoV-2-induced death and reduced viral replication after 24 h of treatment, although the reduction in viral copies was lost after 48 h. Our findings suggest that iminosugars should be urgently investigated as potential SARS-CoV-2 inhibitors.
Dose- and schedule-dependent protective efficacy of Celgosivir in a lethal mouse model for dengue virus infection informs dosing regimen for a proof of concept clinical trial
Antiviral Res 2012 Oct;96(1):32-5.PMID:22867971DOI:10.1016/j.antiviral.2012.07.008.
Celgosivir (6-O-butanoyl castanospermine), a pro-drug of the naturally occurring castanospermine, is an inhibitor of α-glucosidase I and II that is found to be a potent inhibitor of several enveloped viruses including all four serotypes of dengue virus. We showed previously that the compound fully protected AG129 mice from lethal infection with a mouse adapted dengue virus at a dose of 50mg/kg twice daily (BID) for 5days and was effective even after 48h delayed treatment. Here we show that the protection by Celgosivir is dose- and schedule-dependent and that a twice-a-day regimen of 50, 25 or 10mg/kg is more protective than a single daily dose of 100mg/kg. Treatment with 50mg/kg BID castanospermine had comparable efficacy as 25mg/kg BID Celgosivir, suggesting that Celgosivir is approximately twice as potent as castanospermine with respect to in vivo antiviral efficacy. Pharmacokinetics (PK) studies of Celgosivir in mice showed that it rapidly metabolized to castanospermine. Simulation of the PK data with the survival data for the various doses of Celgosivir tested suggests that the steady-state minimum concentration is a critical parameter to note in choosing dose and schedule. These results influenced the selection of the dose regimen for a proof-of-concept clinical trial of Celgosivir as a treatment against dengue fever.
Efficacy and safety of Celgosivir in patients with dengue fever (CELADEN): a phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial
Lancet Infect Dis 2014 Aug;14(8):706-715.PMID:24877997DOI:10.1016/S1473-3099(14)70730-3.
Background: Dengue infection is the most common mosquito-borne viral disease worldwide, but no suitable antiviral drugs are available. We tested the α-glucosidase inhibitor Celgosivir as a treatment for acute dengue fever. Methods: To establish eligibility for inclusion in a phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial, individuals aged 21-65 years who had had a fever (≥38°C) for less than 48 h, met at least two criteria indicating probable dengue infection, and had a positive result on a dengue point-of-care test kit or PCR assay were referred for screening at a centre in Singapore between July 30, 2012, and March 4, 2013. Using a web-based system, we randomly assigned patients who met full inclusion criteria after screening (1:1; random permuted block length four) to Celgosivir (initial 400 mg loading dose within 6 h of randomisation, followed by 200 mg every 12 h for a total of nine doses) or matched placebo. Patients and the entire study team were masked to group assignment. The primary endpoints were mean virological log reduction (VLR) from baseline for days 2, 3, and 4, and area under the fever curve (AUC) for a temperature above 37°C from 0 h to 96 h. Efficacy analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01619969. Findings: We screened 69 patients and randomly assigned 50 (24 to Celgosivir, 26 to placebo). Mean VLR was greater in the Celgosivir group (-1·86, SD 1·07) than in the placebo group (-1·64, 0·75), but the difference was non-significant (-0·22, 90% CI -0·65 to 0·22; one-sided p=0·203). The mean AUC was also higher in the Celgosivir group (54·92, SD 31·04) than in the placebo group (40·72, 18·69), but again the difference was non-significant (14·20, 90% CI 2·16-26·25; one-sided p=0·973). We noted similar incidences of adverse events between groups. Interpretation: Although generally safe and well tolerated, Celgosivir does not seem to reduce viral load or fever burden in patients with dengue. Funding: STOP Dengue Translational Clinical Research.