NIM811 ((Melle-4)cyclosporin) ((Melle-4)cyclosporin; SDZ NIM811 ((Melle-4)cyclosporin)) 是一种口服生物可利用的线粒体通透性转换和亲环素双重抑制剂，在体外对丙型肝炎病毒具有有效的活性(丙肝病毒)。
NIM811 (SDZ NIM811) is a potent mitochondrial permeability transition inhibitor. Sequence: Cyclo[{Aaa}-{Abu}-{Sar}-Ile-Val-Leu-Ala-{D-Ala}-Leu-Leu-Val].
NIM811 is a potent inhibitor of HCV RNA replication in the replicon cells. NIM811 induces a concentration-dependent reduction of HCV RNA in the replicon cells with an IC50 of 0.66 μM at 48 h. Furthermore, a greater than three-log10 viral RNA reduction is achieved after treating the cells with as little as 1 μM of NIM811 for 9 days. In addition, the combination of NIM811 with alpha interferon significantly enhances anti-HCV activities without causing any increase of cytotoxicity[1]. NIM811 blocks the mitochondrial permeability transition induced by calcium and inorganic phosphate. NIM811 blocks cell killing and prevents in situ mitochondrial inner membrane permeabilization and depolarization during tumor necrosis factor-α-induced apoptosis to cultured rat hepatocytes[2].
NIM811 significantly blunts mitochondrial depolarization. Prevention of mitochondrial depolarization by NIM811 attenuates liver injury, stimulates regeneration and improves liver function and survival[3].
[1]. Ma S, et al. NIM811, a cyclophilin inhibitor, exhibits potent in vitro activity against hepatitis C virus alone or in combination with alpha interferon. Antimicrob Agents Chemother. 2006 Sep;50(9):2976-82. [2]. Waldmeier PC, et al. Inhibition of the mitochondrial permeability transition by the nonimmunosuppressive cyclosporin derivative NIM811. Mol Pharmacol. 2002 Jul;62(1):22-9. [3]. Rehman H, et al. NIM811 prevents mitochondrial dysfunction, attenuates liver injury, and stimulates liverregeneration after massive hepatectomy. Transplantation. 2011 Feb 27;91(4):406-12.
Cell experiment: | The antiviral activity and cytotoxicity of compounds are determined using an HCV replicon cell line (Huh-Luc/neo-ET) containing a luciferase reporter gene. Briefly, 5,000 replicon cells are seeded in each well of 96-well tissue culture plates and are allowed to attach in complete culture medium without G418 overnight. On the next day, the culture medium is replaced with medium containing serially diluted NIM811 in the presence of 10% FBS and 0.5% DMSO. After a 48-h NIM811 treatment, the remaining luciferase activities in the cells are determined[1]. |
Animal experiment: | Mice: Male C57BL/6 mice (8-12 weeks) are gavaged with NIM811, 10 mg/kg or an equal volume of vehicle containing 8.3% polyethoxylated castor oil and 8.3% ethanol at 2 h before surgery. Mice undergo massive hepatectomy or sham-operation under ether anesthesia. NIM811 (5 mg/kg) or vehicle is gavaged daily post-operatively for 2 days. Mice are observed for 21 days for survival[3]. |
参考文献: [1]. Ma S, et al. NIM811, a cyclophilin inhibitor, exhibits potent in vitro activity against hepatitis C virus alone or in combination with alpha interferon. Antimicrob Agents Chemother. 2006 Sep;50(9):2976-82. | |
动态评分
0.0