Abstract:
A compound series capable of reversing the antiviral effect of Ribavirin (RBV) against H1N1 was
identified from a high throughput screen designed to discover compounds capable of increasing the
fidelity of the RNA-dependent RNA polymerase (RDRP) n ribovirus quasispecies. Two lead compounds,
RIC-1 (EC50 of 78.4 nM) and RIC-2 (EC50 of 217 nM), returned viral growth to control levels by
completely inhibiting the antiviral activity of RBV. Both compounds demonstrated a loss of activity
when incubated at 37°C in media only, losing functionality within 3 hours. Incubation of RIC-1 or RIC-2
with cells for only 2.5 minutes, however, was able to maintain viral growth by inhibiting RBV for the
full 72 hour growth period. Subsequent testing showed the RIC series was not effective against a second
mutagen, 5-fluorouracil, and RIC-2 did not prevent or slow the development of antiviral resistance when
viral populations were grown in the presence of Zanamivir. Furthermore, RIC-1 was ineffective in
alleviating inhibition of the inosine 5’-monophosphate dehydrogenase (IMPDH) pathway by the
inhibitor mycophenolic acid (MPA). Anti-RBV activity was relieved by increasing the concentration of
RBV, suggesting the RIC series acts to competitively inhibit RBV. The mechanism of action associated
with the RIC compound series is still unclear; however, it appears to act independent of the intended
function of RDRP fidelity modification.
