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Celgosivir (MBI 3253) Sale

(Synonyms: MBI 3253; MDL 28574; MX3253) 目录号 : GC32191

Celgosivir (MBI 3253) (MBI 3253; MDL 28574; MX3253) 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。

Celgosivir (MBI 3253) Chemical Structure

Cas No.:121104-96-9

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实验参考方法

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.
[2]. 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.
[3]. 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.
[4]. 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.

产品描述

Celgosivir (MBI 3253; MDL 28574; MX3253) is a novel α-glucosidase I inhibitor, an enzyme that plays a critical role in viral maturation by initiating the processing of the N-linked oligosaccharides of viral envelope glycoproteins.[1]

The quantity of THP-1 cells is 1 × 105 , cells were washed once with media and replaced with 500 μl with a serial 4-fold dilution starting from 200 μM or 50 μM.[3]

Celgosivir, stored at 100 mg/ml in PBS at 30 °C, were diluted with PBS before each dosing to obtain 1 mg/200 μl (50 mg/kg) or 0.2 mg/200 μl (10 mg/kg). [3]

[1]. Durantel D. Celgosivir, an alpha-glucosidase I inhibitor for the potential treatment of HCV infection. Curr Opin Investig Drugs. 2009 Aug, 10(8):860-70. [2]. Whitby K et al. Action of celgosivir (6 O-butanoyl castanospermine) against the pestivirus BVDV: implications for thetreatment of hepatitis C. Antivir Chem Chemother, 2004 May, 15(3):141-51. [3]. Satoru Watanabe,Kitti Wing-Ki Chan et al. Optimizing celgosivir therapy in mouse models of dengue virus infection of serotypes 1 and 2: The search for a window for potential therapeutic efficacy. Antiviral Research, March 2016, Pages 10-19.

Chemical Properties

Cas No. 121104-96-9 SDF
别名 MBI 3253; MDL 28574; MX3253
Canonical SMILES O[C@@H]1[C@]2([H])[C@@H](O)[C@H](O)[C@@H](OC(CCC)=O)CN2CC1
分子式 C12H21NO5 分子量 259.3
溶解度 Soluble in DMSO 储存条件 Store at -20°C
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1 mg 5 mg 10 mg
1 mM 3.8565 mL 19.2827 mL 38.5654 mL
5 mM 0.7713 mL 3.8565 mL 7.7131 mL
10 mM 0.3857 mL 1.9283 mL 3.8565 mL
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Research Update

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.

Towards antiviral therapies for treating dengue virus infections

Curr Opin Pharmacol 2016 Oct;30:1-7.PMID:27367615DOI:10.1016/j.coph.2016.06.002.

Dengue virus is an emerging human pathogen that poses a huge public health burden by infecting annually about 390 million individuals of which a quarter report with clinical manifestations. Although progress has been made in understanding dengue pathogenesis, a licensed vaccine or antiviral therapy against this virus is still lacking. Treatment of patients is confined to symptomatic alleviation and supportive care. The development of dengue therapeutics thus remains of utmost importance. This review focuses on the few molecules that were evaluated in dengue virus-infected patients: balapiravir, chloroquine, lovastatin, prednisolone and Celgosivir. The lessons learned from these clinical trials can be very helpful for the design of future trials for the next generation of dengue virus inhibitors.

伪-glucosidase inhibitors as host-directed antiviral agents with potential for the treatment of COVID-19

Biochem Soc Trans 2020 Jun 30;48(3):1287-1295.PMID:32510142DOI:10.1042/BST20200505.

The ongoing COVID-19 pandemic, caused by SARS-CoV-2, has pushed the health systems of many countries to breaking point and precipitated social distancing measures that have crippled economic activities across the globe. A return to normality is unlikely until effective therapeutics and a vaccine are available. The immediacy of this problem suggests that drug strategies should focus on repurposing approved drugs or late-stage clinical candidates, as these have the shortest path to use in the clinic. Here, we review and discuss the role of host cell N-glycosylation pathways to virus replication and the drugs available to disrupt these pathways. In particular, we make a case for evaluation of the well-tolerated drugs miglitol, Celgosivir and especially miglustat for the treatment of COVID-19.

Murine models of dengue virus infection for novel drug discovery

Expert Opin Drug Discov 2022 Apr;17(4):397-412.PMID:35098849DOI:10.1080/17460441.2022.2033205.

Introduction: Dengue virus (DENV) is the causative agent of the most prevalent human disease transmitted by mosquitoes in tropical and subtropical regions worldwide. At present, no antiviral drug is available and the difficulties to develop highly protective vaccines against the four DENV serotypes maintain the requirement of effective options for dengue chemotherapy. Areas covered: The availability of animal models that reproduce human disease is a very valuable tool for the preclinical evaluation of potential antivirals. Here, the main murine models of dengue infection are described, including immunocompetent wild-type mice, immunocompromised mice deficient in diverse components of the interferon (IFN) pathway and humanized mice. The main findings in antiviral testing of DENV inhibitory compounds in murine models are also presented. Expert opinion: At present, there is no murine model that fully recapitulates human disease. However, immunocompromised mice deficient in IFN-伪/尾 and -纬 receptors, with their limitations, have shown to be the most suitable system for antiviral preclinical testing. In fact, the AG129 mouse model allowed the identification of Celgosivir, an inhibitor of cellular glucosidases, as a promising option for DENV therapy. However, clinical trials still were not successful, emphasizing the difficulties in the transition from preclinical testing to human treatment.

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.