| Description | Raltegravir potassium (MK 0518 potassium salt) salt(MK0518 potassium salt) is a potent integrase (IN) inhibitor, used to treat HIV infection. |
| In vitro | PFV IN带有S217H突变的对Raltegravir的敏感性降低了10倍，其IC50为900 nM。PFV IN的活性仅为WT活性的10%，并且被Raltegravir以200 nM的IC50抑制，这表明与WT IN相比，对IN链转移抑制剂（INSTI）的敏感性大约降低了两倍。S217Q PFV IN对Raltegravir的敏感性与WT酶相同[1]。Raltegravir通过糖苷化作用而非通过肝脏代谢。Raltegravir对HIV-1具有强大的体外活性，其95%抑制浓度为31±20 nM，在人类T淋巴细胞培养中。Raltegravir还对HIV-2有效，当在CEMx174细胞中测试时，IC95为6 nM。Raltegravir的代谢主要通过糖苷化作用。强烈诱导糖苷化酶UGT1A1的药物会显著降低Raltegravir浓度，因此不应使用。Raltegravir对肝脏细胞色素P450活性具有弱抑制作用。Raltegravir不诱导CYP3A4 RNA表达或CYP3A4依赖的睾酮6-β-羟化酶活性[2]。在镁和钙存在下，Raltegravir的细胞渗透性降低[3]。Raltegravir及相关HIV-1整合酶(IN)链转移抑制剂（INSTIs）有效阻断病毒复制[4]。在急性感染的人类淋巴细胞CD4+ T细胞系MT-4和CEMx174中，Raltegravir有效抑制SIVmac251的复制，其EC90在低nM范围内[5]。 |
| In vivo | Raltegravir 通过其单药治疗在进行中的 SIVmac251 感染的非人灵长类动物中引发病毒免疫学改善。有一种非人灵长类动物在接受 Raltegravir 单药治疗后，其病毒载量检测不到[5]。 |
| Cell experiments | Human MT-4 cells are infected for 2 hours with the SIVmac251, HIV-1 (IIIB) and HIV-2 (CDC 77618) stocks at a multiplicity of infection of, approximately, 0.1. Cells are then washed three times in phosphate buffered saline, and suspended at 5 × 105/mL in fresh culture medium (to primary cells 50 units/mL of IL-2 are added) in 96-well plates, in the presence or absence of a range of triplicate raltegravir concentrations (0.0001 μM-1 μM). Untreated infected and mock-infected controls are prepared too, in order to allow comparison of the data derived from the different treatments. Viral cytopathogeniciy in MT-4 cells is quantitated by the methyl tetrazolium (MTT) method (MT-4/MTT assay) when extensive cell death in control virus-infected cell cultures is detectable microscopically as lack of capacity to re-cluster. The capability of MT-4 cells to form clusters after infection. Briefly, clusters are disrupted by pipetting; and, after 2 hours of incubation at 37°C, the formation of new clusters is assessed by light microscopy (100× magnification). Cell culture supernatants are collected for HIV-1 p24 and HIV-2/SIVmac251 p27 core antigen measurement by ELISA. In CEMx174-infected cell cultures, which show a propensity to form syncytia induced by the virus envelope glycoproteins, syncytia are counted, in blinded fashion, by light microscopy for each well at 5 days following infection. |
| Synonyms | MK 0518 potassium salt, Raltegravir potassium salt, 雷特格韦钾盐 |
| molecular weight | 482.51 |
| Molecular formula | C20H20FN6O5·K |
| CAS | 871038-72-1 |
| Storage | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| Solubility | DMSO: 87 mg/mL (180.3 mM) |
| References | 1. Hare, S., et al., Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance. Proc Natl Acad Sci U S A, 2010. 107(46): p. 20057-62. 2. Hicks C, et al. Raltegravir: the first HIV type 1 integrase inhibitor. Clin Infect Dis. 2009 Apr 1;48(7):931-9. 3. Moss DM, et al. Divalent metals and pH alter raltegravir disposition in vitro. Antimicrob Agents Chemother. 2012 Jun;56(6):3020-6. 4. Hare S, et al. Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir (S/GSK1349572). Mol Pharmacol. 2011 Oct;80(4):565-72. 5. Lewis, M.G., et al. Response of a simian immunodeficiency virus (SIVmac251) to raltegravir: a basis for a new treatment for simian AIDS and an animal model for studying lentiviral persistence during antiretroviral therapy. Retrovirology, 2010. 7: p. 21. |