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]。