Alisporivir (DEB-025)
(Synonyms: Debio-025; DEB-025) 目录号 : GC32072
Alisporivir (Debio-025) is a cyclophilin inhibitor molecule with potent anti-hepatitis C virus (HCV) activity.
Cas No.:254435-95-5
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: | Alisporivir is prepared in DMSO at 4 mM and diluted in cell culture medium at the indicated concentrations (0.1, 0.2, 0.3, 0.4, 0.5 μM). UHCV-32 and UHCVcon-57.3 are U-2 OS human osteosar coma-derived cell lines inducibly expressing the entire open reading frame derived from the HCV H77 prototype and consensus clones, respectively. Cell viability is measured by trypan blue exclusion analysis. HCV protein expression in these cells is induced by withdrawal of tetracycline from the culture medium. The effect of tetracycline on the naive U2 OS cell line is tested measuring mitochondria-related respiration and reactive oxygen species (ROS) production, which remains unchanged[2]. |
References: [1]. Coelmont L, et al. DEB025 (Alisporivir) inhibits hepatitis C virus replication by preventing a cyclophilin A induced cis-trans isomerisation in domain II of NS5A. PLoS One. 2010 Oct 27;5(10):e13687. | |
Alisporivir (Debio-025) is a cyclophilin inhibitor molecule with potent anti-hepatitis C virus (HCV) activity.
[1] Coelmont L, et al. PLoS One. 2010 Oct 27;5(10):e13687.
| Cas No. | 254435-95-5 | SDF | |
| 别名 | Debio-025; DEB-025 | ||
| Canonical SMILES | O[C@@H]([C@](C(N[C@H](C(N([C@@H](C(N([C@H](C(N[C@H](C(N([C@H]1CC(C)C)C)=O)C(C)C)=O)C(C)C)CC)=O)C)C)=O)CC)=O)([H])N(C([C@@H](N(C([C@](N(C([C@@H](N(C([C@@](NC([C@@H](NC1=O)C)=O)([H])C)=O)C)CC(C)C)=O)C)([H])CC(C)C)=O)C)C(C)C)=O)C)[C@H](C)C/C=C/C | ||
| 分子式 | C63H113N11O12 | 分子量 | 1216.64 |
| 溶解度 | DMSO : ≥ 100 mg/mL (82.19 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 | 0.8219 mL | 4.1097 mL | 8.2194 mL |
| 5 mM | 0.1644 mL | 0.8219 mL | 1.6439 mL |
| 10 mM | 0.0822 mL | 0.411 mL | 0.8219 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。
HCV1b genome evolution under selective pressure of the cyclophilin inhibitor Alisporivir during the DEB-025-HCV-203 phase II clinical trial
Infect Genet Evol 2016 Oct;44:169-181.PMID:27374748DOI:10.1016/j.meegid.2016.06.050.
Major advances have revolutionized the HCV antiviral treatment field, with interferon-free combinations of direct-acting antivirals (DAAs) resulting into success rates of >90% for all HCV genotypes. Nevertheless, viral eradication at a global level stills remains challenging, stimulating the continued search for new affordable pan-genotypic drugs. To overcome selection of drug resistant variants, targeting host proteins can be an attractive mechanism of action. Alisporivir (Debio 025) is a potent pan-genotypic host-targeting antiviral agent, acting on cyclophilin A, which is necessary for HCV replication. The efficacy and safety of three different oral doses of Alisporivir in combination with pegylated interferon-α2a given over a period of four weeks, was investigated in a randomized, double-blind and placebo-controlled phase IIa clinical trial, in 90 treatment-naïve subjects infected with chronic hepatitis C, wherefrom 58 HCV1b samples were selected for genetic sequencing purposes. Sequencing results were used to study the HCV genome for amino acid changes potentially related with selective pressure and resistance to Alisporivir. By comparing baseline and on-treatment sequences, a large variation in proportion of amino acid changes was detected in all treatment arms. The NS5A variant D320E, which was previously identified during in vitro resistance selection and resulted in 3.6-fold reduced Alisporivir susceptibility, emerged in two subjects in the Alisporivir monotherapy arm. However, emergence of D320E appeared to be associated only with concurrent viral load rebound in one subject with 0.8log10IU/ml increase in HCV RNA. In general, for all datasets, low numbers of positions under positive selective pressure were observed, with no significant differences between naïve and treated sequences. Additionally, incomplete sequence information for some of the 22 patients and the low number of individuals per treatment arm, is limiting the power to assess the association of Alisporivir or interferon treatment with the observed amino acid changes.
Profile of Alisporivir and its potential in the treatment of hepatitis C
Drug Des Devel Ther 2013;7:105-15.PMID:23440335DOI:10.2147/DDDT.S30946.
Two classes of hepatitis C antiviral agents currently exist, i.e., direct-acting antivirals and host-targeting antivirals. Direct-acting antivirals target viral proteins including NS3/NS4A protease, NS5B polymerase and NS5A protein, while host-targeting antivirals target various host proteins critical for replication of the hepatitis C virus (HCV). Alisporivir is the most advanced host-targeting antiviral in clinical development. Alisporivir blocks HCV replication by neutralizing the peptidyl-prolyl isomerase activity of the abundant host cytosolic protein, cyclophilin A. Due to its unique mechanism of antiviral action, Alisporivir is pangenotypic, provides a high barrier for development of viral resistance, and does not permit cross-resistance to direct-acting antivirals. Alisporivir has an excellent pharmacokinetic and safety profile. Phase I and II clinical studies have demonstrated that Alisporivir causes a dramatic reduction in viral loads in HCV-infected patients. Alisporivir was shown to be highly potent in treatment-naïve and treatment-experienced patients with genotype 1 as well as in those with genotypes 2 or 3. Low viral breakthrough rates were observed and the most frequent clinical and laboratory adverse events associated with Alisporivir in combination with pegylated interferon-alpha and ribavirin were similar to those associated with pegylated interferon-alpha and ribavirin used alone. A laboratory abnormality observed in some patients receiving Alisporivir is hyperbilirubinemia, which is related to transporter inhibition and not to liver toxicity. The most recent clinical results suggest that Alisporivir plus other direct-acting antivirals should provide a successful treatment option for difficult-to-treat populations, such as nonresponders to prior interferon-alpha therapy and patients with cirrhosis. In conclusion, Alisporivir represents an attractive candidate component of future interferon-free regimens.
SARS-coronavirus-2 replication in Vero E6 cells: replication kinetics, rapid adaptation and cytopathology
J Gen Virol 2020 Sep;101(9):925-940.PMID:32568027DOI:10.1099/jgv.0.001453.
The sudden emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the end of 2019 from the Chinese province of Hubei and its subsequent pandemic spread highlight the importance of understanding the full molecular details of coronavirus infection and pathogenesis. Here, we compared a variety of replication features of SARS-CoV-2 and SARS-CoV and analysed the cytopathology caused by the two closely related viruses in the commonly used Vero E6 cell line. Compared to SARS-CoV, SARS-CoV-2 generated higher levels of intracellular viral RNA, but strikingly about 50-fold less infectious viral progeny was recovered from the culture medium. Immunofluorescence microscopy of SARS-CoV-2-infected cells established extensive cross-reactivity of antisera previously raised against a variety of non-structural proteins, membrane and nucleocapsid protein of SARS-CoV. Electron microscopy revealed that the ultrastructural changes induced by the two SARS viruses are very similar and occur within comparable time frames after infection. Furthermore, we determined that the sensitivity of the two viruses to three established inhibitors of coronavirus replication (remdesivir, Alisporivir and chloroquine) is very similar, but that SARS-CoV-2 infection was substantially more sensitive to pre-treatment of cells with pegylated interferon alpha. An important difference between the two viruses is the fact that - upon passaging in Vero E6 cells - SARS-CoV-2 apparently is under strong selection pressure to acquire adaptive mutations in its spike protein gene. These mutations change or delete a putative furin-like cleavage site in the region connecting the S1 and S2 domains and result in a very prominent phenotypic change in plaque assays.
Inhibition of SARS-CoV-2 Infection by the Cyclophilin Inhibitor Alisporivir (Debio 025)
Antimicrob Agents Chemother 2020 Jun 23;64(7):e00876-20.PMID:32376613DOI:10.1128/AAC.00876-20.
Cyclophilins play a key role in the life cycle of coronaviruses. Alisporivir (Debio 025) is a nonimmunosuppressive analogue of cyclosporine with potent cyclophilin inhibition properties. Alisporivir reduced SARS-CoV-2 RNA production in a dose-dependent manner in Vero E6 cells, with a 50% effective concentration (EC50) of 0.46 ± 0.04 μM. Alisporivir inhibited a postentry step of the SARS-CoV-2 life cycle. These results justify rapidly conducting a proof-of-concept phase 2 trial with Alisporivir in patients with SARS-CoV-2 infection.
Alisporivir, a cyclosporin derivative that selectively inhibits cyclophilin, for the treatment of HCV infection
Curr Opin Investig Drugs 2010 Feb;11(2):213-24.PMID:20112171doi
HCV infection is the primary cause of chronic liver disease. Host cell cyclophilins (Cyps) are essential for efficient HCV replication in hepatocytes, and thus Cyps are regarded as a new target for anti-HCV therapy. Alisporivir (Debio-025), a non-immunosuppressive cyclosporine A derivative that selectively inhibits Cyps, is being developed by Debiopharm SA for the potential oral treatment of HCV infection. In the HCV subgenomic replicon system, Alisporivir suppressed viral replication more potently than cyclosporine A. A phase II clinical trial demonstrated that treatment with Alisporivir alone or combined with PEGylated IFNalpha2a reduced the viral load in patients with chronic HCV infection. The drug was also generally well tolerated. In contrast, a phase I trial of Alisporivir monotherapy in patients with HIV-1 infection suggested that the drug has a limited effect on HIV-1 viral load. Alisporivir was also investigated in animal models of muscular dystrophy, acute myocardial infarction and brain disorders. At the time of publication, two phase II trials, evaluating Alisporivir alone and in combination with PEGylated IFNalpha2a or with PEGylated IFNalpha2a and ribavirin, were ongoing in treatment-naïve patients with HCV-1 infection and in patients with chronic HCV-1 infection who were prior non-responders to PEGylated IFNalpha or ribavirin.