P0683 : Hepatitis C virus NS3-4A protease targets the host factor BNIP1 at a non-canonical cleavage site

Abstract

oral dosing for the ability to form the active AL-335 NTP in dog liver. Results: In the stable genotype (GT) 1b replicon assay, AL-335 exhibited potent antiviral activity with an EC50 of 75nM. In transient chimeric GT-1b replicons with NS5B regions derived from GT 1–4, AL-335 demonstrated pan-genotypic activity with EC50 values between 40–60nM. AL-335 retained activity vs. replicon mutants resistant to non-nucleoside polymerase, NS3/4A protease and NS5A inhibitors. AL-335 was additive or synergistic in all combinations studies. The AL-335 NTP was a potent inhibitor of the HCV NS5B polymerase with an IC50 of 120nM and a Ki of 24nM, and acted as a chain-terminator of RNA synthesis. The AL-335 NTP was not a substrate for human mitochondrial RNA polymerase and demonstrated no inhibition (IC50 >100mM) of human DNA or RNA polymerases. In vitro, the AL-335 NTP was rapidly formed and demonstrated a long intracellular half-life of >24hrs in primary human hepatocytes. Following oral administration to dog at 5mg/kg parent nucleoside equivalent, the AL-335 NTP was formed at high and sustained levels in liver (AL-335 NTP levels at 24hrs: 2.1mM). Conclusions: AL-335 is a potent uridine based nucleotide analog that demonstrates a desirable preclinical profile. The compound is currently advancing in preclinical studies as a potential treatment for CHC.