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Purity: ≥98%
| Targets |
Alisporivir targets cyclophilin A (CypA), a peptidyl-prolyl cis-trans isomerase that serves as a critical host cofactor for hepatitis C virus (HCV) replication. By binding to CypA, Alisporivir disrupts the interaction between CypA and the HCV NS5A protein. This disruption inhibits HCV replication in hepatocytes. Alisporivir also inhibits the replication of various coronaviruses, including MERS-CoV and SARS-CoV. Its mechanism of action is distinct from direct-acting antivirals, as it targets a host protein rather than a viral enzyme, which may confer a higher barrier to resistance.
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| ln Vitro |
CypA, a peptidyl-prolyl cis-trans isomerase and an essential cofactor for HCV replication, is bound by DEB025 [1]. The first member of a novel class of cyclophilin inhibitors that are not immunosuppressive is alisporivir (Debio-025). Alisporivir inhibits the collapse of mitochondrial membrane potential caused by respiration mediated by HCV protein. Together with apoptosis, calcium overload, ROS generation, and malfunction, alisporivir also inhibits HCV protein-mediated mitochondrial dysfunction [2]. Low micromolar dosages of alisporivir prevented SARS-CoV and MERS-CoV from replicating in cell culture experiments. In cell cultures, combination treatment with alisporivir and ICN-1229 boosts anti-MERS-CoV activity [3]. Pretreatment with alisporivir can increase target cells for liver cancer's antigen presentation by 40%, which in turn increases antigen-specific CD8+ T cell activation. On the surface of different cell lines, alisporivir can cause an increase in MHC-I and β-2 microglobulin [4].
In vitro, Alisporivir effectively blocks the replication of HCV in cell culture models. Low micromolar doses of Alisporivir also block the replication of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). When combined with ICN-1229, its antiviral activity against MERS-CoV is further enhanced. Alisporivir prevents HCV protein-mediated mitochondrial dysfunction and collapse of mitochondrial membrane potential. It also induces elevated expression levels of MHC-I molecules and β-2 microglobulin on the surface of various cell lines, enhancing the antigen-presenting capacity of liver cancer target cells. |
| ln Vivo |
In mouse models, alisporivir and ICN-1229 therapy in combination was ineffective in preventing SARS-CoV infection [3].
In vivo, Alisporivir has demonstrated anti-HCV activity in animal models. However, in a mouse model, the combination of Alisporivir and ICN-1229 failed to achieve preventive efficacy against SARS-CoV infection. Despite this, the compound's ability to inhibit cyclophilins and disrupt viral-host interactions has made it a subject of clinical investigation. It has been studied for its potential therapeutic applications in various diseases, including HCV infection and coronavirus infections. Its non-immunosuppressive nature is a key advantage over cyclosporine A, making it a safer candidate for antiviral therapy. |
| Enzyme Assay |
The in vitro assays for Alisporivir measure its binding to cyclophilin A and its ability to inhibit cyclophilin activity. These assays typically involve incubating recombinant cyclophilin A with a peptidyl-prolyl cis-trans isomerase substrate in the presence of varying concentrations of Alisporivir. The inhibition of isomerase activity is then measured spectrophotometrically. To assess its antiviral activity, HCV replicon assays are used, where human hepatoma cells harboring a replicating HCV subgenomic RNA are treated with Alisporivir, and viral RNA replication is quantified by real-time PCR or luciferase reporter activity.
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| Cell Assay |
In vitro cell-based assays for Alisporivir are conducted using HCV replicon cell lines or cells infected with coronaviruses. In a typical HCV replicon assay, cells are treated with Alisporivir at various concentrations, and after incubation, the levels of HCV RNA are measured. The EC50, which is the concentration that inhibits 50% of viral replication, is determined from dose-response curves. For coronavirus studies, cells are infected with the virus and then treated with Alisporivir. Viral replication is quantified by measuring viral titers or by detecting viral proteins via immunofluorescence. These assays confirm the compound's antiviral activity and allow for the calculation of its selectivity index.
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| Animal Protocol |
In vivo animal experiments for Alisporivir have been conducted in mouse models of viral infection. In one study, the combination of Alisporivir and ICN-1229 was tested for preventive efficacy against SARS-CoV infection in a mouse model, but it failed to achieve significant protection. Other studies have evaluated its efficacy in HCV models, though specific protocols are not detailed in standard product descriptions. Typically, these studies involve administering Alisporivir orally or by injection to infected animals and monitoring viral load in the blood or tissues over time. The compound's ability to reduce viral load and improve survival is assessed compared to a control group.
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| ADME/Pharmacokinetics |
Alisporivir is a synthetic cyclophilin inhibitor with a chemical structure related to cyclosporine A. It is orally bioavailable. For research use, it is typically supplied as a solid powder. Its solubility in DMSO and other organic solvents is documented. For storage, it is recommended to keep the powder at -20°C for long-term stability. Detailed pharmacokinetic parameters such as half-life, volume of distribution, and clearance have been studied in the context of clinical development. However, these specific values are not detailed in standard product descriptions available for research purposes.
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| Toxicity/Toxicokinetics |
Detailed toxicity data for Alisporivir is not provided in standard product descriptions. As a non-immunosuppressive analogue of cyclosporine A, it is designed to have a better safety profile than the parent compound. In preclinical studies, its safety would be assessed in animal models. However, specific toxicity data, such as LD50 or organ toxicity, are not detailed. The compound has been investigated in clinical trials for HCV and other viral infections, where its safety and tolerability would have been evaluated. As with all research chemicals, standard laboratory safety precautions should be followed when handling Alisporivir.
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| References |
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| Additional Infomation |
Alispolivir is a homocyclic peptide with anticoronavirus activity. Alispolivir has been investigated for the treatment of hepatitis C and chronic hepatitis C. Alispolivir is a non-immunosuppressive analog of cyclosporine A and an inhibitor of cycloavidin, possessing potential antiviral activity. After oral administration, alispolivir targets and inhibits human host cycloavidin, thereby inhibiting the replication of hepatitis C virus (HCV) in hepatocytes. Alispolivir may also inhibit the replication of various coronaviruses. Furthermore, it may inhibit mitochondrial cycloavidin D, which regulates the opening of the mitochondrial permeability transition pore (mPTP). This may help prevent cell death and tissue damage.
Drug Indications Treatment of chronic hepatitis C Alisporivir (Debio-025) is a research compound and is not approved for any clinical or therapeutic use. It is a non-immunosuppressive cyclophilin inhibitor that was developed as an antiviral agent. Its primary mechanism of action involves disrupting the interaction between cyclophilin A and the HCV NS5A protein, thereby inhibiting HCV replication. It has also shown broad-spectrum antiviral activity against coronaviruses. Alisporivir has been investigated in clinical trials for the treatment of chronic hepatitis C and other viral infections. However, its development may have been discontinued or repurposed. It remains a valuable research tool for studying cyclophilin biology and viral-host interactions. |
| Exact Mass |
1215.857
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| CAS # |
254435-95-5
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| PubChem CID |
11513676
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| Appearance |
White to off-white solid powder
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| Density |
1.0±0.1 g/cm3
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| Boiling Point |
1294.2±65.0 °C at 760 mmHg
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| Flash Point |
736.5±34.3 °C
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| Vapour Pressure |
0.0±0.6 mmHg at 25°C
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| Index of Refraction |
1.467
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| LogP |
3.84
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
12
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| Rotatable Bond Count |
15
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| Heavy Atom Count |
86
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| Complexity |
2360
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| Defined Atom Stereocenter Count |
13
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| SMILES |
O[C@H]([C@H](C)C/C=C/C)[C@H]1C(N[C@@H](CC)C(N(C)[C@H](C)C(N(CC)[C@H](C(N[C@H](C(N(C)[C@H](C(N[C@@H](C)C(N[C@H](C)C(N(C)[C@@H](CC(C)C)C(N(C)[C@H](C(N(C)[C@H](C(N1C)=O)C(C)C)=O)CC(C)C)=O)=O)=O)=O)CC(C)C)=O)C(C)C)=O)C(C)C)=O)=O)=O
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| InChi Key |
OLROWHGDTNFZBH-XEMWPYQTSA-N
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| InChi Code |
InChI=1S/C63H113N11O12/c1-26-29-30-40(16)52(75)51-56(79)66-44(27-2)59(82)68(20)43(19)58(81)74(28-3)49(38(12)13)55(78)67-48(37(10)11)62(85)69(21)45(31-34(4)5)54(77)64-41(17)53(76)65-42(18)57(80)70(22)46(32-35(6)7)60(83)71(23)47(33-36(8)9)61(84)72(24)50(39(14)15)63(86)73(51)25/h26,29,34-52,75H,27-28,30-33H2,1-25H3,(H,64,77)(H,65,76)(H,66,79)(H,67,78)/b29-26+/t40-,41+,42-,43-,44+,45+,46+,47+,48+,49+,50+,51+,52-/m1/s1
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| Chemical Name |
(3S,6S,9S,12R,15S,18S,21S,24S,27R,30S,33S)-25,30-diethyl-33-((1R,2R,E)-1-hydroxy-2-methylhex-4-en-1-yl)-6,9,18-triisobutyl-3,21,24-triisopropyl-1,4,7,10,12,15,19,27,28-nonamethyl-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontan-2,5,8,11,14,17,20,23,26,29,32-undecaone
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| Synonyms |
Debio 025 Debio-025Debio025UNII-VBP9099AA6 UNIL 025 DEB025.
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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. |
| 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) |
DMSO : ≥ 100 mg/mL (~82.19 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.62 mg/mL (2.15 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (2.05 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
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.
Long Term Follow-up Study to Assess Durability of Sustained Virologic Response in Alisporivir-treated Hepatitis C Patients
CTID: NCT02753699
Phase: Phase 3 Status: Completed
Date: 2016-08-26
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