Lomibuvir (VX-222) 是丙型肝炎病毒 NS5B 聚合酶的一种非核苷变构抑制剂，Kd值为 17 nM，已证明具有临床疗效。Lomibuvir 抑制 1b/Con1 型HCV亚基因组复制子，EC50为 5.2 nM。Lomibuvir 优先抑制延长的 RNA 合成，而非从头合成的 RNA。

Lomibuvir (VX-222) is a selective, non-nucleoside allosteric inhibitor of HCV NS5B polymerase (RdRp) with a Kd of 17 nM. Lomibuvir inhibits the 1b/Con1 HCV subgenomic replicon with an EC 50 of 5.2 nM. Lomibuvir preferentially inhibits elongative RNA synthesis rather than de novo -initiated RNA synthesis [1].

Lomibuvir (VX-222) inhibits WT HCV 1b/Con1 replicon with an EC 50 of 5.2 nM. Lomibuvir inhibits M423T, L419M and I482L (mutant replicons) with EC 50 s of 79.8, 563.1, 45.3 nM, respectively. Lomibuvir reduces de novo initiation slightly but also exhibits strong inhibition of primer extension. The IC 50 of Lomibuvir for primer-extended RNA synthesis is 31 nM [1]. Lomibuvir is a non-nucleoside, allosteric inhibitor of the hepatitis C virus NS5B polymerase with demonstrated clinical efficacy [2].

In rats and dogs, VCH-222 displays fine pharmacokinetic pro?le, including low total body clearance and excellent oral bioavailability (greater than 30%) and good ADME properties. VCH-222 is biotransformed by several enzymes (CYP1A1, 2A6, 2B6, 2C8, CYP 3A4, UGT1A3) and is predicted to be actively transported in liver and excreted mainly intact in bile or as glucuronide adducts. [3]

Anti-NS5B activity assay: The inhibitory effect of VX-222 on HCV NS5B activity is measured by evaluating the amount of radiolabeled UTP incorporated by the C-terminal ?21 truncated version of enzyme in a newly synthesized RNA using a homopolymeric RNA template / primer namely poly rA / oligo dT. Quantitative detection of incorporated radioactivity is done using a liquid scintillation counter. The in vitro kinetics of inhibition of HCV NS5B from genotype 1b strain BK by VX-222 are determined using the C-terminal ?21 truncated version of NS5B. VX-222 (1 to 1.5 μM) is tested in the presence of 10 to 75 μM nonradioactive UTP mixed with 0.89 to 6.70 μCi of [α-33P]-labeled UTP. RNA-dependent-RNA polymerase reactions are allowed to proceed for 18 min at 22 °C.

Huh7.5 cells harboring HCV RNA replicons are trypsinized and plated into 48-well plates at a concentration of 4 × 104 cells/well. The next day the medium is changed and VX-222 is added in 200 μL of complete medium. After 48 hours, total RNA is extracted and viral RNAs are quanti?ed by real-time reverse transcription-PCR (RT-PCR). The effective drug concentrations that reduced HCV RNA replicon levels by 50% (EC50) are calculated by nonlinear regression analysis with log curve ?tting.(Only for Reference)

1026785-55-6

C25H35NO4S

445.61

VCH-222;VX-222

H2O:<1 mgml
Ethanol:82 mg/mL (184 mM)
DMSO:82 mg/mL (184 mM)
Powder: -20°C for 3 years
In solvent: -80°C for 2 years