PF-429242 efficiently blocked SKI-1/S1P-mediated processing and subsequent activation of SREBP2 in cell culture and a small animal model. The toxicity profile and pharmacokinetic properties made PF-429242 a promising candidate for a novel anti-arenaviral drug. PF-429242 was able to block the biosynthesis of fusion-active mature GPC of the OW arenaviruses LCMV and LASV and showed potent anti-viral activity against LCMV and LASV in acute infection in cultured cells. These findings suggested the feasibility of using PF-429242 as a novel anti-arenaviral drug. Here we extended these studies and show that PF-429242 is broadly active anti-arenaviral drug that acts in synergy with ribavirin. Moreover, PF-429242 efficiently and rapidly cleared persistent virus from infected cells. Interruption of drug treatment did not result in re-emergence of infection, indicating that PF-429242 treatment resulted in virus extinction.
| Cell Experiment | |
|---|---|
| Cell lines | 293T cells |
| Preparation method | At 5 h posttransfection, the medium was replaced with fresh medium including the indicated concentration of PF-429242. At 36 h posttransfection, cell lysates were prepared (1% NP-40, 50 mM Tris-HCl [pH 8.0], 62.5 mM EDTA, 0.4% sodium deoxycholate) and subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), followed by Western blotting (WB). |
| Concentrations | 1, 10, or 30 μM |
| Incubation time | 36 h |
| Animal Experiment | |
|---|---|
| Animal models | A129 mice |
| Formulation | saline |
| Dosages | 2 mg, 1 mg and 0.4 mg per mouse |
| Administration | i.v. |
| Molecular Weight | 409.56 |
| Formula | C25H35N3O2 |
| CAS Number | 947303-87-9 |
| Solubility (25°C) | 10 mM in DMSO |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
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