Voclosporin (ISAtx-247)是一种具有口服活性的钙调神经磷酸酶抑制剂，Voclosporin可通过抑制钙调神经磷酸酶来阻断IL-2的表达和T细胞介导的免疫反应，同时稳定肾脏足细胞以减少肾脏损伤。
Cas No.:515814-01-4
Sample solution is provided at 25 µL, 10mM.
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Voclosporin (ISAtx-247) is an orally active calcineurin inhibitor. Voclosporin blocks IL-2 expression and T cell-mediated immune responses by inhibiting calcineurin, while stabilizing renal podocytes to reduce kidney injury[1-2]. Voclosporin is used for the treatment of lupus nephritis[3-4].
In vitro, human peripheral blood CD4+ T cells were stimulated with anti-CD3/CD28 antibodies and then treated with Voclosporin (10mg/ml) for 48 hours. Voclosporin significantly inhibited the secretion of cytokines including IL-2, IL-6, IFN-γ, TNF-α, IL-4, IL-5, IL-9, IL-13, IL-17A, IL-17F, IL-22, and IL-10, and attenuated the expression of cell surface activation markers such as CD25, CD44, and CD69[5].
In vivo, in a cerebral ischemia-reperfusion model, mice were intraperitoneally administered Voclosporin (25mg/kg; 30 minutes in advance) and then subjected to middle cerebral artery occlusion (MCAO) and rtPA reperfusion. Voclosporin significantly improved neurological function scores, reduced cerebral infarction volume, alleviated blood-brain barrier damage and brain edema, and modulated the inflammatory response by promoting the polarization of microglia/macrophages toward the M2 phenotype[6]. In a desiccating stress (DS) dry eye model, mice were treated with Voclosporin (0.2% ophthalmic solution; 1 drop) topically twice daily, starting from the first day of DS induction and continuing for either 5 or 10 days. Voclosporin significantly improved corneal barrier function, increased conjunctival goblet cell density, and reduced the generation of pathogenic CD4+ T cells[7].
References:
[1] van Gelder T, Lerma E, Engelke K, et al. Voclosporin: a novel calcineurin inhibitor for the treatment of lupus nephritis. Expert Rev Clin Pharmacol. 2022 May;15(5):515-529.
[2] Heo YA. Voclosporin: First Approval. Drugs. 2021 Apr;81(5):605-610.
[3] Saxena A, Ginzler EM, Gibson K, et al. Safety and Efficacy of Long-Term Voclosporin Treatment for Lupus Nephritis in the Phase 3 AURORA 2 Clinical Trial. Arthritis Rheumatol. 2024 Jan;76(1):59-67.
[4] Menn-Josephy H, Hodge LS, Birardi V, et al. Efficacy of Voclosporin in Proliferative Lupus Nephritis with High Levels of Proteinuria. Clin J Am Soc Nephrol. 2024 Mar 1;19(3):309-318.
[5] Lindemann A, Roth D, Koop K, et al. Protective effect of the novel calcineurin inhibitor voclosporin in experimental colitis. Front Med (Lausanne). 2023 Jun 9;10:1177450.
[6] Zheng Y, Ma S, Sun W, et al. Voclosporin promotes neurological function recovery by inhibiting inflammation and maintaining blood-brain barrier integrity following rtPA reperfusion after MCAO in mice. Inflammopharmacology. 2025 Jun;33(6):3317-3328.
[7] Alam J, de Souza RG, Yu Z, et al. Calcineurin Inhibitor Voclosporin Preserves Corneal Barrier and Conjunctival Goblet Cells in Experimental Dry Eye. J Ocul Pharmacol Ther. 2020 Nov;36(9):679-685.
Voclosporin (ISAtx-247)是一种具有口服活性的钙调神经磷酸酶抑制剂，Voclosporin可通过抑制钙调神经磷酸酶来阻断IL-2的表达和T细胞介导的免疫反应，同时稳定肾脏足细胞以减少肾脏损伤[1-2]。Voclosporin可用于狼疮性肾炎的相关治疗[3-4]。
在体外，Voclosporin（10mg/ml）处理经抗CD3/CD28抗体刺激的人外周血CD4+ T细胞48小时，Voclosporin显著抑制IL-2、IL-6、IFN-γ、TNF-α、IL-4、IL-5、IL-9、IL-13、IL-17A、IL-17F、IL-22和IL-10的细胞因子分泌，减弱CD25、CD44和CD69等细胞表面活化标志物的表达[5]。
在体内，在脑缺血再灌注模型中，Voclosporin（25mg/kg；提前30min）腹腔注射小鼠，随后通过大脑中动脉阻塞（MCAO）及rtPA再灌注处理小鼠，Voclosporin显著改善神经功能评分、减少脑梗死体积、减轻血脑屏障损伤和脑水肿，并通过促进小胶质细胞/巨噬细胞向M2型极化来调节炎症反应[6]。Voclosporin（0.2%眼用溶液；1滴）每天两次局部点眼处理，用于诱导干燥应激（DS）干燥眼模型的小鼠（从干燥应激第1天开始，持续5天或10天）。Voclosporin显著改善了角膜屏障功能、增加了结膜杯状细胞密度，并减少了致病性CD4+ T细胞的产生[7]。
| Cell experiment [1]: | |
Cell lines | CD4+ T lymphocytes |
Preparation Method | MACS-enriched human CD4+ T lymphocytes were cultured in IMDM-based medium supplemented with 10% FCS and 1% penicillin/streptomycin. The cells were stimulated with anti-CD3 (1μg/mL) and anti-CD28 (2μg/mL) antibodies, or with PMA (25ng/mL) and ionomycin (1μg/mL). Subsequently, the cells were incubated in the presence or absence of either Voclosporin (10mg/ml) or Cyclosporine A (8.3µM) for 48 hours. |
Reaction Conditions | 10mg/ml; 48 hours. |
Applications | Voclosporin markedly reduced the secretion of multiple cytokines, including IL-2, IL-6, IFN-γ, TNF-α, IL-4, IL-5, IL-9, IL-13, IL-17A, IL-17F, IL-22, and IL-10, in culture supernatants. Voclosporin also significantly blocked the transcription of IL-2, IFN-γ, TNF, IL-17A, IL-17F, and IL-10 genes. Voclosporin attenuated the upregulation of the T cell activation surface markers CD25, CD44, and CD69 induced by polyclonal stimulation. |
| Animal experiment [2]: | |
Animal models | C57BL/6J mice |
Preparation Method | Mice were intraperitoneally administered Voclosporin (25mg/kg). After 30min, the mice were subjected to focal cerebral ischemia by middle cerebral artery occlusion (MCAO) for 45 minutes. Immediately after filament withdrawal, the mice underwent rtPA (recombinant tissue plasminogen activator) reperfusion. Neurological and biochemical analyses were performed 24 hours and 72 hours following reperfusion. |
Dosage form | 25mg/kg; i.p.; single injection |
Applications | Voclosporin treatment significantly improved neurological function scores (mNSS, Longa, beam walking test) and reduced cerebral infarction volume in mice at 72 hours following rtPA reperfusion. Voclosporin alleviated blood-brain barrier (BBB) injury, as evidenced by reduced Evans blue extravasation and lower brain water content, thereby improving BBB integrity. Furthermore, Voclosporin reduced the expression of pro-inflammatory cytokines (IL-1β, TNF-α) and increased the expression of anti-inflammatory cytokines (IL-4, IL-10) in the brain. Voclosporin also promoted the polarization of microglia/macrophages from the M1 type (iNOS+/Iba-1+) to the M2 type (Arg-1+/Iba-1+). |
References: | |
| Cas No. | 515814-01-4 | SDF | |
| 别名 | ISAtx-247 | ||
| Canonical SMILES | C=C/C=C/C[C@@H](C)[C@H]([C@]1([H])N(C([C@](N(C([C@@H](N(C([C@](N(C([C@H](NC([C@@H](NC([C@H](CC(C)C)N(C)C([C@@](C(C)C)([H])NC([C@H](CC(C)C)N(C)C(CN(C)C([C@H](CC)NC1=O)=O)=O)=O)=O)=O)C)=O)C)=O)C)([H])CC(C)C)=O)C)CC(C)C)=O)C)([H])C(C)C)=O)C)O | ||
| 分子式 | C63H111N11O12 | 分子量 | 1214.62 |
| 溶解度 | DMSO : ≥ 50 mg/mL (41.17 mM);Water : < 0.1 mg/mL (insoluble) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 823.3 μL | 4.1165 mL | 8.233 mL |
| 5 mM | 164.7 μL | 823.3 μL | 1.6466 mL |
| 10 mM | 82.3 μL | 411.7 μL | 823.3 μL |
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- Purity: >98.00% Appearance: A solid
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