Lomibuvir (VCH-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].

HCV NS5B 1a:0.94-1.2 μM

Lomibuvir (VX-222) is an effective non-nucleoside, allosteric inhibitor of the hepatitis C virus NS5B polymerase, exhibiting strong clinical efficacy. It demonstrates potent inhibition against the wild-type HCV 1b/Con1 replicon with an EC50 of 5.2 nM and against mutant replicons M423T, L419M, and I482L with EC50s of 79.8, 563.1, and 45.3 nM, respectively. Besides slightly hindering de novo initiation, Lomibuvir prominently impairs primer extension, illustrated by an IC50 of 31 nM for primer-extended RNA synthesis.

In rats and dogs, Lomibuvir displays fine pharmacokinetic prole, including low total body clearance and excellent oral bioavailability (greater than 30%) and good ADME properties. Lomibuvir 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]