Alisporivir (DEB-025)是一种环加氧酶抑制剂，具有强效的抗丙型肝炎病毒特性。
Cas No.:254435-95-5
Sample solution is provided at 25 µL, 10mM.
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Alisporivir (DEB-025) is a cyclophilin inhibitor with potent anti-HCV properties[1]. As a cyclosporine analog, Alisporivir inhibits the immunoproteasome and suppresses viral protein folding and maturation[2]. Alisporivir is uaually used in HCV treatment research[3].
In vitro, Alisporivir (0.01-10μM; 3h) inhibits SARS-CoV-2 RNA production and dose-dependently reduces infected cells dose-dependently in Vero E6 cells with an EC50 of 0.46μM[4]. Alisporivir (5μM; 24h) increased cell viability, restored mitochondrial membrane potential and mitochondrial permeability transition pore (MPT pore) opening activity to control levels, reduced colocalization of mitochondria and lysosomes, and normalized Parkin gene expression in mouse lung endothelial cells under hyperglycemic conditions[5].
In vivo, Alisporivir (5mg/kg/day; intraperitoneal injection; 4 weeks) increased calcium uptake by skeletal muscle mitochondria, reduced expression of Pink1 and Parkin genes, and led to fragmentation and decreased mean size of mitochondria in skeletal muscles of dystrophin-deficient C57BL/10ScSn-mdx mice[6]. Alisporivir (5mg/kg/day; intraperitoneal injection; 4 weeks) significantly decreased serum creatine kinase, AST, and LDH levels, improved muscle function, increased sarcomere size, normalized mitochondrial ultrastructure, improved calcium retention capacity, enhanced respiratory control ratio, and reduced lipid peroxidation in the skeletal muscle of dystrophin-deficient mdx mice[7].
References:
[1] Coelmont L, Hanoulle X, Chatterji U, 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;5(10):e13687.
[2] Esser-Nobis K, Schmidt J, Nitschke K, Neumann-Haefelin C, Thimme R, Lohmann V. The cyclophilin-inhibitor alisporivir stimulates antigen presentation thereby promoting antigen-specific CD8(+) T cell activation. J Hepatol. 2016;64(6):1305-1314.
[3] Gallay PA, Lin K. Profile of alisporivir and its potential in the treatment of hepatitis C. Drug Des Devel Ther. 2013;7:105-115.
[4] Softic L, Brillet R, Berry F, et al. Inhibition of SARS-CoV-2 Infection by the Cyclophilin Inhibitor Alisporivir (Debio 025). Antimicrob Agents Chemother. 2020;64(7):e00876-20.
[5] Starinets VS, Serov DA, Penkov NV, Belosludtseva NV, Dubinin MV, Belosludtsev KN. Alisporivir Normalizes Mitochondrial Function of Primary Mouse Lung Endothelial Cells Under Conditions of Hyperglycemia. Biochemistry (Mosc). 2022;87(7):605-616.
[6] Dubinin MV, Starinets VS, Mikheeva IB, Belosludtsev KN. Effect of Alisporivir on Calcium Ion Transport and Mitophagy in Skeletal Muscle and Heart Mitochondria in Dystrophin-Deficient Mice. Bull Exp Biol Med. 2022;172(6):695-700.
[7] Dubinin MV, Starinets VS, Talanov EY, Mikheeva IB, Belosludtseva NV, Belosludtsev KN. Alisporivir Improves Mitochondrial Function in Skeletal Muscle of mdx Mice but Suppresses Mitochondrial Dynamics and Biogenesis. Int J Mol Sci. 2021;22(18):9780.
Alisporivir (DEB-025)是一种环加氧酶抑制剂，具有强效的抗丙型肝炎病毒特性[1]。作为一种环孢素类似物，Alisporivir可抑制免疫蛋白酶体，进而抑制病毒蛋白的折叠和成熟[2]。Alisporivir通常用于丙型肝炎治疗研究[3]。
在体外实验中，Alisporivir（0.01-10μM；3小时）可在Vero E6细胞中抑制SARS-CoV-2 RNA的产生，并以剂量依赖性方式减少感染细胞，EC50为0.46μM[4]。Alisporivir（5μM；24 小时）在高糖条件下可提高小鼠肺血管内皮细胞的存活率，将线粒体膜电位和线粒体通透性转换孔（MPT孔）的开放活性恢复至对照水平，减少线粒体与溶酶体的共定位，并使Parkin基因表达正常化[5]。
在体内实验中，Alisporivir（5mg/kg/天；腹腔注射；4周）可增加dystrophin缺陷型C57BL/10ScSn-mdx小鼠骨骼肌线粒体的钙摄取量，降低Pink1和Parkin基因的表达，并导致线粒体发生碎裂，降低线粒体平均体积[6]。Alisporivir（5mg/kg/天；腹腔注射；4周）显著降低了dystrophin缺陷型mdx小鼠血清中的肌酸激酶、天门冬氨酸氨基转移酶（AST）和乳酸脱氢酶（LDH）水平，改善了肌肉功能，增加了肌节长度，使骨骼肌中的线粒体超微结构正常化，提高了线粒体的钙保留能力，增强了呼吸控制率，并减少了脂质过氧化[7]。
| Cell experiment [1]: | |
Cell lines | Mouse lung endothelial cells |
Preparation Method | Endothelial cells were isolated from mouse lung microvessels by indirect magnetic separation. Cells of passage 7-10 with viability estimated by propidium iodide (PI) staining of at least 98% were used in the experiments. Round coverslips (25mm diameter) were placed one at a time into the wells of 6-well plates. A solution of 0.2% gelatin was applied to coverslips, dried, and next a suspension of endothelial cells in the culture medium was added. The cells were cultured for 3 days until confluence level of 90% or more was reached. Hyperglycemia was modeled by cell incubation in a culture medium with an elevated glucose concentration of 30mM for 24h in a CO2 incubator. Control cells were incubated for 24h in a culture medium with a glucose concentration of 5mM. Half of the samples were incubated with 5μM Alisporivir. Alisporivir was added to the culture medium as a solution in DMSO (1 : 2000 dilution), cells without Alisporivir were incubated for 24h after addition of the appropriate volume of DMSO. Cell viability was assessed by Hoechst 33342 /PI staining. A fluorescent dye rhodamine 123 was used to determine potential on the inner mitochondrial membrane. Colocalization of mitochondria and lysosomes in endotheliocytes was assessed using confocal microscopy based on colocalization of fluorescent dyes MitoTracker DeepRed FM (200nM) and LysoTracker Green (50nM) in the cells. |
Reaction Conditions | 5μM; 24h |
Applications | Alisporivir increased cell viability, restored mitochondrial membrane potential and MPT pore opening activity to control levels, and reduced colocalization of mitochondria and lysosomes in mouse lung endothelial cells under hyperglycemic conditions. |
| Animal experiment [2]: | |
Animal models | mdx mice |
Preparation Method | Dystrophin-deficient C57BL/10ScSn-mdx animals (mdx mice) were used in this experiment. After 72h of acclimatization, mice were divided into four treatment groups (n=10 per group): (1) vehicle-treated mice (control); (2) mice treated with Alisporivir. Mice were treated at 8 weeks of age. Alisporivir (1mg/mL) was dissolved in a mixture of DMSO, ethanol, and sterile saline (12.5:25:62.5 v/v%) and administered in doses of 150-200µL (5mg/kg body weight) per mouse interperitoneally every day for up to 4 weeks. Sham-injected controls received solvent alone. At the end of the treatment period, all mice were sacrificed. Blood was collected at the end of all studies for analysis of creatine kinase (CK), lactate dehydrogenase (LDH), and aspartate aminotransferase (AST) levels using the appropriate reagent. Mitochondrial isolation was performed in fresh samples of skeletal muscle tissue (quadriceps of both hindlimbs). The rest of the tissue was stored at -80℃ until analyzed. |
Dosage form | 5mg/kg/day; intraperitoneal injection; 4 weeks |
Applications | Alisporivir significantly decreased serum creatine kinase, AST, and LDH levels and normalized mitochondrial ultrastructure in the skeletal muscle of dystrophin-deficient mdx mice. |
References: | |
| 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 |
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1 mg | 5 mg | 10 mg |
| 1 mM | 821.9 μL | 4.1097 mL | 8.2194 mL |
| 5 mM | 164.4 μL | 821.9 μL | 1.6439 mL |
| 10 mM | 82.2 μL | 411 μL | 821.9 μL |
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