JNJ-9117 is a potent, pan-genotypic hepatitis E virus (HEV) replication inhibitor, inhibits HEV-3 and rat HEV replicon replication with IC50s of 21 nM and 30 nM, respectively.
Compared to Ribavirin (RBV) and Sofosbuvir (SOF), JNJ-9117 is respectively 300- and 30-fold more active against the HEV-3 replicon, 1500- and 40-fold more active against the rat HEV replicon, and 1800- and 100-fold more active against the HEV-1 replicon.
JNJ-9117 also potently inhibits the replication of the HEV-1 and HEV-3 subgenomic replicons in a range of other cell lines, both hepatic (IC50: 10-150 nM) and non-hepatic, including intestinal (IC50: 150-300 nM), neuronal (IC50: 14-900 nM), lung (IC50: 85-145 nM) and the placental
JEG-3 (IC50: ~41 nM) cells.
JNJ-9117 is also active against the HEV-3 83-2-27/luc replicon; a HEV strain from wild boar, which is an important source of zoonotic HEV.
JNJ-9117 significantly lowered viral RNA levels in the supernatant and the expression of HEV ORF2 in hepatic HepG2/C3A cells transfected
with full-length HEV-3 genomic RNA.
JNJ-9117 reduced virus yields in rat HEV-infected cell cultures, with the highest concentration (10 µM) suppressing viral RNA replication to almost undetectable levels, even during the 12d post-treatment period.
JNJ-9117 acts as a phosphorylated guanosine analogue, exerts its antiviral effect against HCV through inhibition of the RNA-dependent RNA polymerase (RdRp) by its 5'-triphosphate metabolite (JNJ-9117-TP) and this in competition with guanosine triphosphate (GTP), resulting in chain termination during viral RNA synthesis.